Refined routes to chlorin building blocks

ABSTRACT

A method of making chlorins comprises the steps of reacting (e.g. condensing) a dipyrrin western half intermediate with an eastern half intermediate to form a tetrahydrobilene, and then cyclizing the tetrahydrobilene to form a chlorin. Intermediates including tetrahydrobilenes useful in such reactions are also described.

RELATED APPLICATIONS

This application claims the benefit of Provisional Application Ser. No.60/289,985, filed May 10, 2001, the disclosure of which is incorporatedby reference herein in its entirety.

STATEMENT OF FEDERAL SUPPORT

This invention was made with Government support under Grant No. GM36238from the National Institutes of Health. The Government has certainrights to this invention.

FIELD OF THE INVENTION

The present invention concerns methods and intermediates useful for thesynthesis of chlorins.

BACKGROUND OF THE INVENTION

A synthetic route that provides access to chlorin building blocksbearing substituents at the meso- and/or β-positions has recently beendescribed (Strachan, et al. (2000) J. Org. Chem. 65:3160-3172;Balasubramanian, et al. (2000) J. Org. Chem. 65:7919-7929). In additionto selected patterns of functional group handles at the perimeter of themacrocycle, each chlorin bears a geminal dimethyl group to lock in thehydrogenation level yet lacks steric congestion or other unwantedfunctionality around the reduced ring. The synthesis involves theconstruction of an Eastern half and a Western half, which are joined toform the chlorin macrocycle in the final step (Scheme 1). Thisconvergent coupling of the Eastern half and Western half is performed ina two-flask procedure involving acid-catalyzed condensation to give adihydrobilene-a, followed by metal-mediated oxidative cyclization togive the chlorin. The Eastern half, a bromodipyrromethane-monocarbinol,is readily available by the acylation and bromination of adipyrromethane at the 1- and 9-positions, respectively, followed byreduction. The Western half is a dihydrodipyrrin (1). The Western halfhas limited stability and generally must be prepared from the stablenitro-hexanone pyrrole precursor and used within a few days.

In our initial search for routes to a suitable Western half, weinvestigated the synthesis of a tetrahydrodipyrrin via an intermediatetetrahydrodipyrrin N-oxide (comprised of a pyrrole and a pyrrolineN-oxide)(Strachan, et al. (2000) J. Org. Chem. 65:3160-3172). Theformation of N-oxides by cyclization followed by deoxygenation affords aconvenient entry to a number of heterocycles (Katritzky and Lagowski,Chemistry of the Heterocyclic N-Oxides, Academic Press: London and NewYork, 1971, pp. 166-231; Ochiai, E. Aromatic Amine Oxides, Elsevier:Amsterdam, 1967, pp. 184-209; Albini, A.; Pietra, S. HeterocyclicN-Oxides, CRC Press: Boca Raton, 1991, pp. 120-134). Indeed, pyrrolineN-oxides played a central role throughout Todd's studies related to thesynthesis of vitamin B₁₂ (Bonnett, et al. (1959) J. Chem. Soc.2094-2102; Bonnett et al. (1959) J. Chem. Soc. 2102-2104; Bonnett, etal. (1959) J. Chem. Soc. 2105-2108; Brown et al. (1959) J. Chem. Soc.2109-2116; Brown et al. (1959) J. Chem. Soc. 2116-2122; Clark, et al.(1959) J. Chem. Soc. 2123-2127; Bowering et al. (1963) Annalen669:106-113; Brown, et al. (1965) J. Chem. Soc. 2337-2340; Brown et al.(1966) Tetrahedron, Suppl. 8, Part 1:15-26; Black, et al. (1976) J.Chem. Soc. Perkin Trans. I (18):1942-1943; Black, et al. (1976) J. Chem.Soc. Perkin Trans. I (18):1944-1950; Black, et al. (1976) J. Chem. Soc.Perkin Trans. I (18):1951-1954; Alderson et al. (1976) J. Chem. Soc.Perkin Trans. I (18):1955-1960). Battersby synthesized atetrahydrodipyrrin N-oxide, converted it to the correspondingtetrahydrodipyrrin, and upon reaction with a1-bromo-9-bromomethyldipyrrin in the presence of copper acetate obtainedthe copper chlorin in 6.9% yield (2.8 mg) (Battersby, et al. (1984) J.Chem. Soc. Perkin Trans. 1 (12):2725-2732). Though Battersby's pyrrolecomponent was substituted with one ester and two alkyl groups, the routeemployed also proved suitable for our synthesis of a tetrahydrodipyrrinN-oxide incorporating an unsubstituted pyrrole unit (Strachan, et al.(2000) J. Org. Chem. 65:3160-3172). Thus, cyclization of anitro-hexanone pyrrole (2) afforded the corresponding tetrahydrodipyrrinN-oxide (3), but we were unable to, deoxygenate the cyclic nitrone andform the tetrahydrodipyrrin Western half (4) (Strachan, et al. (2000) J.Org. Chem. 65:3160-3172). We resorted to the cyclization of thenitro-hexanone pyrrole 2 with NaOMe/THF followed by TiCl₃ inNH₄OAc-buffered solution, forming the dihydrodipyrrin 1 directly(without isolating the N-oxide) in yields of 20-30% (Strachan, et al.(2000) J. Org Chem. 65:3160-3172; Balasubramanian, et al. (2000) J. Org.Chem. 65:7919-7929).

SUMMARY OF THE INVENTION

A first aspect of the present invention is a method of making a chlorinof Formula X:

wherein:

-   -   M is a metal, such as a metal selected from the group consisting        of Cu, Zn, Mg, Pt, Pd, Sn and Al, or M is absent;    -   K¹, K² and K⁴ are independently selected atoms, such as atoms or        hetero atoms independently selected from the group consisting of        N, O, S, Se, Te, and CH (preferably not CH, and most preferably        N);    -   K³is N;    -   S¹, S², S³, S⁴ S⁵, S⁶, S⁷, S⁸, S⁹, S¹⁰, S¹¹, S¹², S¹³, and S¹⁴        are independently selected substituents, such as substituents        selected from the group consisting of H, aryl, phenyl,        cycloalkyl, alkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio,        perfluoroalkyl, perfluoroaryl, pyridyl, cyano, thiocyanato,        nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl, imido,        amido, and carbamoyl (e.g., H or alkyl). Preferably at least S⁸        and S¹⁴ are both not H (e.g., both are alkyl). In addition, from        one to four of S¹, S², S³, S⁴ S⁵, S⁶, S⁷, S⁸, S⁹, S¹⁰, S¹¹, S¹²,        S¹³, and S⁴ may optionally be independently selected linking        groups Q, such as linking groups Q are of the formula:        R¹—R²_(n)R³—Y        wherein:    -   n is from 0 or 1 to 5 or 10;    -   R³ may be present or absent;    -   R¹, R², and R³ are each independently selected from the group        consisting of ethene, ethyne, aryl, and heteroaryl groups, which        aryl and heteroaryl groups may be unsubstituted or substituted        one or more times with H, aryl, phenyl, cycloalkyl, alkyl,        alkenyl, alkynyl, halogen, alkoxy, alkylthio, perfluoroalkyl,        perfluoroaryl, pyridyl, cyano, thiocyanato, nitro, amino,        alkylamino, acyl, sulfoxyl, sulfonyl, imido, amido, and        carbamoyl; and    -   Y is a protected or unprotected reactive substituent, such as a        reactive substituent selected from the group consisting of        hydroxy, thio, seleno, telluro, ester, carboxylic acid, boronic        acid, phenol, silane, sulfonic acid, phosphonic acid,        alkylthiol, formyl, halo, alkenyl, alkynyl, haloalkyl, alkyl        phosphonate, alkyl sulfonate, alkyl carboxylate, and alkyl        boronate groups.

The method comprises oxidatively cyclizing a tetrahydrobilene of FormulaXI:

wherein Z is selected from the group consisting of halo, alkoxy, andacyloxy (preferably in an organic solvent in the presence of a base, anoxidant and a metal salt MX_(n), where X is an anion, and n is 2-3, toproduce a compound of Formula X above), and then optionally displacingmetal M to create a free base chlorin.

A second aspect of the present invention is a method of making atetrahydrobilene of Formula XI:

wherein: K¹, K² K³ and K⁴ are as described above; S¹, S², S³, S⁴ S⁵, S⁶,S⁷, S⁸, S⁹, S¹⁰, S¹¹, S¹², S¹³, and S¹⁴ are as described above; and Z isas described above. The method comprising condensing a compound ofFormula WH with a compound of Formula EH

(preferably in an organic solvent in the presence of an acid) to form atetrahydrobilene of Formula XI.

A third aspect of the present invention is a tetrahydrobilene of FormulaXI:

wherein: K¹, K² K³ and K⁴ are as described above; S¹, S², S³, S⁴ S⁵, S⁶,S⁷, S⁸, S⁹, S¹⁰, S¹¹, S¹², S¹³, and S¹⁴ are as described above; and Z isas described above.

A fourth aspect of the present invention is a compound of Formula WH:

wherein:

-   -   K¹ is as described above; and S¹, S², S⁷, S⁸, S⁹, S¹², S¹³, and        S¹⁴ are as described above (preferably subject to the proviso        that S¹ and S² are not simultaneously alkyl).

A fifth aspect of the present invention is a method of making a compoundof Formula WH:

wherein: K¹ is as given above, S¹, S², S⁷, S⁸, S⁹, S¹², S¹³, and S¹⁴ areas given above (not necessarily subject to the proviso noted immediatelyabove).

The method comprises reacting a compound of Formula III

in an organic solvent (preferably in the presence of Ti(0)) to form thecompound of Formula WH.

A sixth aspect of the present invention is a compound according toFormula III:

wherein: K¹ is as given above; and S¹, S², S⁷, S⁸, S⁹, S¹², S¹³, and S¹⁴are as given above (preferably subject to the proviso that S¹ and S² arenot simultaneously alkyl).

A seventh aspect of the present invention is a method of making acompound of Formula III:

wherein: K¹ is as given above, and S¹, S², S⁷, S⁸, S⁹, S¹², S¹³, and S¹⁴are as given above. The method comprises cyclizing a compound of FormulaII:

(preferably in an organic solvent under reducing conditions, for examplein the presence of zinc oxid and acetic acid) to produce a compound ofFormula III.

An eighth aspect of the present invention is a compound of Formula II:

wherein K¹ is as given above, and S¹, S², S⁷, S⁸, S⁹, S¹², S¹³, and S¹⁴are as given above.

A ninth aspect of the present invention is a compound of Formula X:

wherein:

-   -   M is as given above,    -   K¹, K² K³ and K⁴ are as given above;    -   S¹, S², S³, S⁴ S⁵, S⁶, S⁸, S⁹, S¹⁰, S¹¹, S¹², and S¹⁴ are as        given above;    -   S⁷ and S¹³ are together=O; and    -   from one to four of S¹, S², S³, S⁴ S⁵, S⁶, S⁸, S⁹, S¹⁰, S¹¹,        S¹², and S¹⁴ are independently selected linking groups Q as        given above. In a particular embodiment at least S¹ is a linking        group Q, and in a paraticular embodiment S¹ is a halogen such as        iodo.

The foregoing and other objects and aspects of the present invention areexplained in greater detail in the drawings herein and the specificationset forth below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the effect of the concentration of TFA on the condensationof Eastern half (6a-OH) and Western half (4). The yield shown refers tothe amount of chlorin formed upon treatment of the crude product to theoxidation conditions (analogous to a one-flask reaction) followed byUV-Vis spectroscopy.

FIG. 2 shows the effect of the duration of the condensation of Easternhalf (6a-OH) and Western half (4) on the ultimate yield of chlorin. Theyield shown refers to the amount of chlorin formed upon treatment of thecrude product to the oxidation conditions (analogous to a one-flaskreaction) followed by UV-Vis spectroscopy.

FIG. 3 shows the spectral evolution of the conversion of 7a to Zn-8aupon treatment to the oxidation conditions [tetrahydrobilene-a (7a) (10mM), AgTf (3 mol equiv), Zn(OAc)₂ (15 mol equiv),2,2,6,6-tetramethylpiperidine (15 mol equiv) in CH₃CN at reflux in air].Time points shown were taken at 1 min, 3 min, 8 min, 15 min, 35 min, 1h, 2 h, and 5 h. The absorption peaks at the Soret band and at theQ_(y)(0,0) band increase with time. The absorption peak at 505 nm risesand declines with time (from lowest to highest intensity the times were1 min, 5 h, 2 h, 3 min, 1 h, 35 min, 8 min, and 15 min).

FIG. 4 shows the yield of chlorin Zn-8a as a function of time upontreatment of 7a to the oxidation conditions [tetrahydrobilene-a (7a) (10mM), AgTf (3 mol equiv), Zn(OAc)₂ (15 mol equiv),2,2,6,6-tetramethylpiperidine (15 mol equiv) in CH₃CN at reflux in air].The yield was determined by absorption spectroscopy (ε₆₀₉=43,600M⁻¹cm⁻¹) in toluene. Solid circles, THF; open circles, CH₃CN.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The term “substituent” as used in the formulas herein, particularlydesignated by S or S^(n) where n is an integer, in a preferredembodiment refer to electron-rich or electron-deficient groups(subunits) that can be used to adjust the redox potential(s) and/orspatial properties of the subject compound. Preferred substituentsinclude, but are not limited to, H, aryl, phenyl, cycloalkyl, alkyl,alkenyl, alkynyl, halogen, alkoxy, alkylthio, perfluoroalkyl,perfluoroaryl, pyridyl, cyano, thiocyanato, nitro, amino, alkylamino,acyl, sulfoxyl, sulfonyl, amido, and carbamoyl. In certain embodiments,a substituted aryl group is attached to a porphyrin or a porphyrinicmacrocycle, and the substituents on the aryl group are selected from thegroup consisting of aryl, phenyl, cycloalkyl, alkyl, alkenyl, alkynyl,halogen, alkoxy, alkylthio, perfluoroalkyl, perfluoroaryl, pyridyl,cyano, thiocyanato, nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl,amido, and carbamoyl. Additional substituents include, but are notlimited to, 4-chlorophenyl, 4-trifluoromethylphenyl, and4-methoxyphenyl. Preferred substituents provide a redox potential rangeof less than about 5 volts, preferably less than about 2 volts, morepreferably less than about 1 volt.

The term “aryl” refers to a compound whose molecules have the ringstructure characteristic of benzene, naphthalene, phenanthrene,anthracene, etc. (i.e., either the 6-carbon ring of benzene or thecondensed 6-carbon rings of the other aromatic derivatives). Forexample, an aryl group may be phenyl (C₆H₅) or naphthyl (C₁₀H₇). It isrecognized that the aryl group, while acting as substituent can itselfhave additional substituents (e.g. the substituents provided for S^(n)in the various formulas herein).

The term “alkyl” refers to a paraffinic hydrocarbon group, typically C1to C4, which may be derived from an alkane by dropping one hydrogen fromthe formula. Examples are methyl (CH₃—), ethyl (C₂H₅—), propyl(CH₃CH₂CH₂—), isopropyl ((CH₃)₂CH—).

The term “alkenyl” refers to a hydrocarbon group, typically C2 to C4,derived from the corresponding alkyl and which contains at least onedouble bond (e.g., butadienyl).

The term “alkynyl” refers to a hydrocarbon group, typically C2 to C4,derived from the corresponding alkyl and which contains at least onetriple bond (e.g., butadienyl).

The term “halogen” refers to one of the electronegative elements ofgroup VIIA of the periodic table (fluorine, chlorine, bromine, iodine,astatine).

The term “perfluoroalkyl” refers to an alkyl group where every hydrogenatom is replaced with a fluorine atom.

The term “perfluoroaryl” refers to an aryl group where every hydrogenatom is replaced with a fluorine atom.

The term “pyridyl” refers to an aryl group where one CR unit is replacedwith a nitrogen atom.

The term “sulfoxyl” refers to a group of composition RS(O)— where R issome alkyl, aryl, cycloalkyl, perfluoroalkyl, or perfluoroaryl group.Examples include, but are not limited to methylsulfoxyl, phenylsulfoxyl,etc.

The term “sulfonyl” refers to a group of composition RSO₂— where R issome alkyl, aryl, cycloalkyl, perfluoroalkyl, or perfluoroaryl group.Examples include, but are not limited to methylsulfonyl, phenylsulfonyl,p-toluenesulfonyl, etc.

The term “carbamoyl” refers to the group of compositionR¹(R²)NC(O)—where R¹ and R² are H or some alkyl, aryl, cycloalkyl,perfluoroalkyl, or perfluoroaryl group. Examples include, but are notlimited to N-ethylcarbamoyl, N,N-dimethylcarbamoyl, etc.

The term “amido” refers to the group of composition R¹CON(R²)— where R¹and R² are H or some alkyl, aryl, cycloalkyl, perfluoroalkyl, orperfluoroaryl group. Examples include, but are not limited to acetamido,N-ethylbenzamido, etc.

The term “acyl” refers to an organic acid group in which the —OH of thecarboxyl group is replaced by some other substituent (RCO—). Examplesinclude, but are not limited to acetyl, benzoyl, etc.

In preferred embodiments, when a metal is designated by “M” or “Me”,where n is an integer, it is recognized that the metal may be associatedwith a counterion.

As noted above, the present invention provides a method of making achlorin of Formula X:

wherein:

-   -   M is a metal, such as a metal selected from the group consisting        of Cu, Zn, Mg, Pt, Pd, Sn and Al, or M is absent;    -   K¹, K² and K⁴ are atoms, such as atoms or hetero atoms        independently selected from the group consisting of N, O, S, Se,        Te, and CH (CH is less preferred and N is most preferred);    -   K³ is N;    -   S¹, S², S³, S⁴ S⁵, S⁶, S⁷, S⁸, S⁹, S¹⁰, S¹¹, S¹², S¹³, and S¹⁴        are independently selected substituents, such as substituents        selected from the group consisting of H, aryl, phenyl,        cycloalkyl, alkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio,        perfluoroalkyl, perfluoroaryl, pyridyl, cyano, thiocyanato,        nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl, imido,        amido, and carbamoyl.

In addition, from one to four of S¹, S², S³, S⁴ S⁵, S⁶, S⁷, S⁸, S⁹, S¹⁰,S¹¹, S¹², S¹³, and S¹⁴ may optionally be independently selected linkinggroups Q, for example linking groups Q of the formula:R¹—R²_(n)R³—Ywherein:

-   -   n is from 0 or 1 to 5 or 10;    -   R³ may be present or absent;    -   R¹, R², and R³ are each independently selected from the group        consisting of ethene, ethyne, aryl, and heteroaryl groups, which        aryl and heteroaryl groups may be unsubstituted or substituted        one or more times with H, aryl, phenyl, cycloalkyl, alkyl,        alkenyl, alkynyl, halogen, alkoxy, alkylthio, perfluoroalkyl,        perfluoroaryl, pyridyl, cyano, thiocyanato, nitro, amino,        alkylamino, acyl, sulfoxyl, sulfonyl, imido, amido, and        carbamoyl; and    -   Y is a protected or unprotected reactive substituent, for        example a reactive substituent selected from the group        consisting of hydroxy, thio, seleno, telluro, ester, carboxylic        acid, boronic acid, phenol, silane, sulfonic acid, phosphonic        acid, alkylthiol, formyl, halo, alkenyl, alkynyl, haloalkyl,        alkyl phosphonate, alkyl sulfonate, alkyl carboxylate, and alkyl        boronate groups.

The method comprises oxidatively cyclizing a tetrahydrobilene of FormulaXI:

wherein Z is selected from the group consisting of halo, alkoxy, andacyloxy (preferably Br) (preferably in an organic solvent in thepresence of a base, an oxidant and a metal salt MX_(n), where X is ananion, and n is 2-3, to produce a compound of Formula X above), and thenoptionally displacing metal M to create a free base chlorin. Anysuitable solvent may be employed, including polar or nonpolar solventsand protic or aprotic solvents. Suitable bases that may be used in thereaction include but are not limited to piperidine and2,2,6,6-tetramethylpiperidine. Any suitable oxidant may be used,including simply air, oxygen, silver iodate, etc. In a preferredembodiment the cyclizing step is carried out in the presence of a silversalt such as silver triflate. The optional step of displacing metal Mmay be carried out with an acid in accordance with known techniques.

Structurally in compounds described herein, S¹ and S⁵ may beindependently selected trans-substituted linking groups Q, or S² and S⁶may be independently selected trans-substituted linking groups Q¹ andQ².

A second aspect of the present invention is a method of making atetrahydrobilene of Formula XI:

wherein K¹, K² K³ and K⁴ are as described above, and S¹, S², S³, S⁴ S⁵,S⁶, S⁷, S⁸, S⁹, S¹⁰, S¹¹, S¹², S¹³, and S¹⁴ are as described above; andZ is as described above. The method comprises condensing a compound ofFormula WH with a compound of Formula EH

(preferably in an organic solvent in the presence of an acid) to form atetrahydrobilene of Formula XI. Any suitable acid may be employed, suchas a Bronsted or Lewis acid, one particular example beingtrifluoroacetic acid. The condensing step is preferably carried outunder nonaqueous conditions. The organic solvent is preferably a polaror nonpolar aprotic solvent, such as acetonitrile, tetrahydrofuran or amixture thereof.

The present invention further provides methods of making compounds ofFormula WH, and the compounds so produced:

wherein K¹ is as given above, and S¹, S², S⁷, S⁸, S⁹, S¹², S¹³, and S¹⁴are as given above. The method comprises reacting a compound of FormulaIII

in an organic solvent (preferably in the presence of Ti(0)) to form thecompound of Formula WH.

A preferred group of compounds of Formula WH are those in which S¹ andS² are not simultaneously alkyl. One particularly preferred embodimentis compounds in which S¹ and S² are not simultaneously either alkyl or H(i.e., S¹ is not H or alkyl, and S² is not H or alkyl). In anotherparticularly preferred embodiment, S¹ and/or S² are independentlyselected from the group consisting of Q, aryl, phenyl, cycloalkyl,alkenyl, alkynyl, halogen, alkoxy, alkylthio, perfluoroalkyl,perfluoroaryl, pyridyl, cyano, thiocyanato, nitro, amino, alkylamino,acyl, sulfoxyl, sulfonyl, imido, amido, and carbamoyl. In anotherparticular preferred embodiment, S¹ and/or S² is a linking group Q asdescribed above.

A further aspect of the present invention is a method of making acompound of Formula III:

wherein: K¹ is as given above, and S¹, S², S⁷, S⁸, S⁹, S¹², S¹³, and S¹⁴are as given above, and the compounds so produced. The method comprisescyclizing a compound of Formula II:

(preferably in an organic solvent and preferably under reducingconditions, such as in the presence of zinc and acetic acid) to producea compound of Formula III.

Synthesis of Oxochlorins. Oxochlorins may be considered as a particulartype of chlorin. Oxochlorins and chlorins have similar spectralproperties but the oxochlorins are more resistant to oxidation than arechlorins. In fact, oxochlorins have oxidation potentials similar tothose of porphyrins whereas chlorins have lower oxidation potentialsthan porphyrins. Thus, broadly speaking, an oxochlorin has the spectralproperties of a chlorin and the oxidation properties of a porphyrin.

The time-honored method for forming oxochlorins employs treatment of aβ-substituted porphyrin with OsO₄ forming the vicinal diol, which uponacid-catalyzed pinacol rearrangement yields the oxochlorin bearing ageminal dialkyl group (Chang, C. K.; Sotiriou, C. J. Heterocyclic Chem.1985, 22:1739-1741). However, application of this approach to porphyrinbuilding blocks bearing specific patterns of substituents at theperimeter of the macrocycle typically results in a mixture ofoxochlorins (Osuka, A., et al., J. Am. Chem. Soc. 1996, 118:155-168).Battersby found that the attempted synthesis of a chlorin by reaction ofan Eastern half and a Western half in the presence of copper acetate inair afforded the oxochlorin directly (Battersby, A. R, et al., J. Chem.Soc. Perkin Trans. 1 1984, 2725-2732). He stated in his paper thatspectral monitoring indicated the chlorin was forming first and thenundergoing oxidation to give the oxochlorin. The same reaction in theabsence of air afforded the chlorin. While the oxochlorin was anundesired byproduct in Battersby's synthesis, the oxochlorinincorporated the keto functionality at a specific site and did not occuras a mixture of isomers.

In our synthesis, we employ zinc acetate in air to, form the chlorinupon reaction of an Eastern half and a Western half. The chlorin soobtained can be oxidized to the oxochlorin, introducing the ketofunctionality adjacent to the geminal dimethyl group by oxidation of theisolated methylene group. Oxidation can be achieved by a variety ofmethods, including treatment with copper acetate and air, or oxidationwith a number of reagents known to oxidize isolated methylene units.Such reagents include SeO₂, MnO₂, and CrO₃.

Statement of Utility. Chlorins (this term including oxochlorins) asdescribed herein are useful for a variety of purposes known to thoseskilled in the art, including but not limited to the production of lightharvesting arrays and solar cells as described in commonly owned,copending U.S. patent applications Ser. No. 09/621,797 and Ser. No.09/621,091, both filed Jul. 21, 2000, the disclosures of both of whichare incorporated by reference herein in their entirety.

The following examples are provided to illustrate certain aspects of theinvention, and are not to be construed as limiting thereof.

EXAMPLE 1 Refined Syntheses of Meso-Substituted Chlorins viaTetrahydrobilene Intermediates

In this Example, we describe a number of refinements that greatlyfacilitate access to chlorin building blocks. The synthesis of a newWestern half (4) built around the tetrahydrodipyrrin nucleus is achievedby the deoxygenation of the corresponding N-oxide (3) under non-acidicconditions. The resulting tetrahydrobilene-a is stable, which enabledrefinements to the conditions for both the condensation and theoxidation. We also have investigated a one-flask synthetic procedure forchlorin formation. Several new Eastern halves have also been preparedfor enhanced solubility of the resulting chlorin building blocks inorganic solvents. The meso-substituted chlorin building blocks are ofinterest in the synthesis of multi-chlorin arrays.

Synthesis of a Tetrahydrodipyrrin Western Half The synthesis of theunsubstituted tetrahydrodipyrrin Western half 4 is shown in Scheme 2.The desired nitro-hexanone pyrrole 2 was prepared frompyrrole-2-carboxaldehyde by reaction with nitromethane, affording2-(2-trans-nitrovinyl)pyrrole, followed by reduction with sodiumborohydride and fluoride-mediated Michael addition of mesityl oxide.Reductive cyclization of 2 in the presence of Zn in acetic acid at roomtemperature as specified by Battersby ((1984) J. Chem. Soc. PerkinTrans. 1 (12):2725-2732) afforded the N-oxide 3 in <40% yield. Abyproduct, observable by TLC analysis and estimated by ¹H NMRspectroscopy to be present in ˜3:2 ratio (3:byproduct), was isolated andassigned the structure shown for 5 (Scheme 2). Noteworthy features ofthe ¹H NMR spectrum of 5 include the following: (1) the presence of tworesonances due to the pyrrole β-protons, in contrast to the threeresonances due to the α- and β-protons exhibited by the N-oxide 3, and(2) disappearance of the singlets assigned to the amino and pyrrolic NHprotons upon exchange with D₂O. The formation of such a cyclic byproductcannot occur with pyrrole precursors bearing a full complement of alkylsubstituents at the α- and β-positions (Battersby, et al. (1984) J.Chem. Soc. Perkin Trans. 1 (12):2725-2732). The same reaction performedin acetic acid diluted 1:1 with ethanol (to lessen the exotherm) andheld at 0° C., with portion-wise addition of the Zn, resulted in a >9:1ratio of 3:5. The residual byproduct 5 was readily removed bychromatography. Under these improved conditions the desired N-oxide 3was isolated in 86% yield.

The next step involved deoxygenation of N-oxide 3 to give thetetrahydrodipyrrin 4. Numerous methods have been developed for thedeoxygenation of heterocyclic N-oxides bearing various functional groups(Katritzky and Lagowski, Chemistry of the Heterocyclic N-Oxides,Academic Press: London and New York, 1971, pp. 166-231; Ochiai, E.Aromatic Amine Oxides, Elsevier: Amsterdam, 1967, pp. 184-209; Albini,A.; Pietra, S. Heterocyclic N-Oxides, CRC Press: Boca Raton, 1991, pp.120-134). For the tetrahydrodipyrrin N-oxide, the ideal deoxygenationmethod must not be strongly acidic to avoid polymerizing the pyrroleunit, and must not cause reduction of the imine. The deoxygenation of 3was examined with a variety of reagents (Zn, NaOH/methanol (den Hertog,et al. (1952) Rec. Trav. Chim. Pays-Bas. 71:1145-1151); Zn, aqueousNH₄Cl/THF ( (Jiu and Mueller (1959) J. Org. Chem. 24:813-818; Aoyagi, etal. (Aug. 1997) Synthesis-Stuttgart 891-894); FeSO₄, aqueous NH₄Cl/CH₃CN(Talik and Plazek (1961) Roczniki Chem. 35:463-473); Mg, AcONH₄/methanol(Hahn and Lesiak (1985) Polish J. Chem. 59:627-629); Fe, AcONH₄/methanol(Hahn and Lesiak (1985) Polish J. Chem. 59:627-629); Ph₃P/toluene (Lu,et al. (1982) Synthesis-Stuttgart 185-186; Read, et al. (1983) Aust. J.Chem. 36:1227-1237); S/toluene (Relyea, et al. (1962) J. Org. Chem.27:477-481); NaN₃/toluene (Di Nunno and Florio (1975) La Chim. E L'Ind.(Milan) 57:243-244); Zn, NaI, Me₃SiCl/CH₃CN (Morita, et al. (1981) Chem.Lett. 921-924); at room temperature and at elevated temperatures but theN-oxide was resistant to deoxygenation with each of these reagents asdetermined by TLC or ¹H NMR analysis. In addition, NaBH_(4/)THF (Kawazoeand Tachibana (1965) Chem. Pharm. Bull. 13(9):1103-1107; Kawazoe andAraki (1968) Chem. Pharm. Bull. 16(5):839-847) reduced the N-oxide andthe double bond affording several products. Treatment with TiCl₃ in abuffered NH₄OAc solution (Battersby, et al. (1984) J. Chem. Soc. PerkinTrans. 1 (12):2725-2732) gave the pyrrolo-atropine byproduct 5 (obtainedpreviously but not identified (Strachan, et al. (2000) J. Org. Chem.65:3160-3172). This failure is in contrast to the successfultransformation (75% yield) achieved by Battersby and coworkers uponapplying the same method to a tetrahydrodipyrrin N¹⁰-oxide whichdiffered from 3 only in bearing one ester and two alkyl substituents onthe pyrrole unit (Battersby, et al. (1984) J. Chem. Soc. Perkin Trans. 1(12):2725-2732). Similar pyrrolo[3.2.1]azabicyclooctane products havebeen reported by rearrangement of tetrahydrodipyrrin derivatives (formedas intermediates in amine+keto-aldehyde condensations in studies ofaging) and a plausible mechanism proposed involving electrophilic attackof the pyrroline imine at the pyrrole 3-position (Xu and Sayre (1999)Chem. Res. Toxicol. 12:862-868).

Application of a procedure for the deoxygenation of N-oxides withTi(0)/THF at room temperature (Malinowski, M. (1987) Synthesis-Stuttgart(8):732-734) to 3 resulted in a variety of decomposition products asdetermined by ¹H NMR spectroscopy. Upon repeating the deoxygenationprocedure with the addition of 2 molar equivalents of triethylamine tothe Ti(0)/THF slurry (to neutralize the HCl liberated from thepreparation of Ti(0)) prior to addition to the solution of 3 in THF, thedesired deoxygenated product 4 was obtained as a crystalline solidfollowing column chromatography. The tetrahydrodipyrrin 4 is quitestable, exhibiting negligible decomposition over one month upon storageat 0° C.

Investigation of the Synthesis of Chlorins. Our prior synthesis ofchlorins involved (1) formation of the bromodipyrromethane-monocarbinol(Eastern half) by NaBH4-reduction of the carbonyl group in the Easternhalf precursor, (2) acid-catalyzed condensation of the Eastern half andthe Western half to obtain the dihydrobilene-a, and (3) oxidativemetal-mediated cyclization to give the chlorin (Strachan, et al. (2000)J. Org. Chem. 65:3160-3172; Balasubramanian, et al. (2000) J. Org. Chem.65:7919-7929). All three steps were done in succession on the same day.However, condensation of 4 and 6a-OH (100 mM TFA in CH₃CN at roomtemperature) followed by oxidation under the conditions employed with 1(excess AgIO₃, Zn(OAc)₂ and piperidine in anhydrous toluene at 80° C.)gave chlorin Zn-8a in only 7% yield. Similarly, reaction of 4 and 6c-OHafforded chlorin Zn-8c in 10% yield.

Studies of the Condensation. To understand whether the low yields ofchlorin originated in the condensation process or the metal-mediatedoxidative cyclization process, we sought to isolate the putativetetrahydrobilene-a, a linear tetrapyrrole derivative formed bycondensation of the Western half and the Eastern half. The condensationof 4 and Eastern half 6a-OH (100 mM each) was performed at roomtemperature in CH₃CN containing 100 mM TFA (Eq 1). TLC analysis of thereaction mixture after 3 min. showed the presence of a new component.Chromatographic workup afforded the tetrahydrobilene-a 7a in 72% yield.The ¹H NMR spectrum of the tetrahydrobilene-a showed resonancescharacteristic of the respective Western half 4 and Eastern halfprecursor 6a. The three signals (7.75, 8.05, 9.29 ppm) assigned to thepyrrolic NH units each appeared as a broad multiplet. The appearance ofmultiple signals is not unexpected: the tetrahydrobilene-a containsthree chiral centers and the isolated product can comprise up to eightdiastereomers. Bilanes and derivatives are known to be sensitive tooxidation as well as attack by electrophilic species (e.g., acids), andto undergo intermolecular exchange of the pyrrole rings (Xue and Scott(Sep. 1998) Tetrahedron Lett. 39(37):6651-6654). However, thetetrahydrobilene-a sample showed no decomposition upon storage as asolid for several months or in a solution of CDCl₃ for more than twoweeks under argon in the refrigerator.

The surprising stability of the tetrahydrobilene-a and access to ˜500 mgquantities of this material enabled us to explore the reactionconditions of the separate condensation and oxidation steps. To modifythe conditions of the condensation, the concentration of TFA and thereaction time were examined. The condensation of Western half 4 andEastern half 6a-OH was performed for a given period of time; forquantitation, the resulting tetrahydrobilene-a 7a was subjected to theoxidative cyclization to form the chlorin. The yield of the chlorinZn-8a was then determined by UV-vis spectroscopy. Refined conditions forthe oxidative cyclization were employed (vide infra); these conditionsemploy AgTf, Zn(OAc)₂ and 2,2,6,6-tetramethylpiperidine in CH₃CN atreflux in air for 4.5 h.

The effect of the concentration of TFA (10 mM to 316 MM) was examined atroom temperature for condensations of 30 min in CH₃CN. The results areshown in FIG. 1. The chlorin was formed in 51% yield upon use of 100 mMTFA. By contrast, the reaction of the dihydrodipyrrin (1) was performedwith 10 mM reactants and 10 mM TFA, and yields of chlorin were 10-20%.

Two possible side reactions during acid catalyzed condensation were ofconsiderable concern, including rearrangement of the Western half andacidolytic scrambling: (1) A likely mechanism for formation of byproduct5 involves electrophilic attack of the positively charged imine (ornitrone) on the 3-position of the pyrrole. Treatment of 4 (100 mM) underthe same acid catalysis conditions (100 mM TFA in CH₃CN at roomtemperature) gave a ratio of 95:5 for compounds 4:5 after 30 min but˜20:80 after 12 h. The same reaction with 1 M TFA gave ˜15:85 after 30min. These results show that the rearrangement of the Western half 4 tothe byproduct 5 occurs under acid catalysis but the reaction is too slowto be competitive with the condensation with an Eastern half giving thetetrahydrobilene-a. (2) A key concern upon exposure of dipyrromethanesto acidic media is the occurrence of acidolysis yielding fragments thatcan recombine to form products with undesired substitution patterns(i.e., scrambling) (Littler, et al. (1999) J. Org. Chem. 64:2864-2872).We have found that dipyrromethane-carbinols (and the resultingporphyrinogens) are stable to modest concentrations of TFA in CH₃CN butthat scrambling occurs within 30 min upon exposure to 100 mM TFA (Rao,et al. (2000) J. Org. Chem. 65:7323-7344; Rao et al. (2000) J. Org.Chem. 65:1084-1092). LD-MS analysis of the crude reaction mixture showedno scrambling with condensations employing 100 mM TFA. The absence ofscrambling in the condensation of the Eastern and Western halves athigher acid concentration than in dipyrromethane condensations can beexplained by consideration of the basicity of the different reactants.The weakly basic nature of the pyrrolic unit in a dipyrromethane(protonated 2-methylpyrrole has pK_(a)=−0.21) (Chiang and Whipple (1963)J. Am. Chem. Soc. 85:2763-2767) provides little capacity for bufferingof the acid in reactions of the dipyrromethane. By comparison, thepyrroline motif in the Western half is basic (protonated2,4,4-trimethyl-Δ¹-pyrroline has pK_(a)=7.6) (Bonnett, et al. (1959) J.Chem. Soc. 2087-2093). With equal concentrations of TFA and the Westernhalf (100 mM each) the latter likely buffers the former, affording aneffective acidity within the range that safely avoids acidolysis of thedipyrromethane or tetrahydrobilene-a species.

The time course of the condensation for reactions with 100 mM TFA atroom temperature is shown in FIG. 2. These results show that thereaction is rapid and the yield changes only slightly over the course of2 h, with a slight peak around 30 min. In summary, a condensation for 30min at room temperature in CH₃CN containing 100 mM TFA results in thehighest yield of chlorin.

Studies of the Metal-Mediated Oxidative Cyclization. While very littleis known either about the intermediates or the sequence of events inthis process, consideration of the formal transformations in the overallprocess guided our thinking in the development of reaction conditions.The role of the oxidant is to remove 6 electrons and 6 protons. The roleof the base is to neutralize the acetic acid (2 equiv) formed upon zincinsertion and the HBr formed upon aromatization, and perhaps tofacilitate imine-enamine tautomerization. The role of the metal complexis to template the electrocyclization. The role of the silver salt is tofacilitate dehydrobromination. The overall process is expected to becomplex. For example, oxidation is likely to occur in multiple steps,interspersed in which may be complexation and other processes.

The conversion of the tetrahydrobilene-a 7a to the zinc chlorin Zn-8awas examined under a variety of conditions. The conditions employedpreviously used AgIO₃ (15 mol equiv) Zn(OAc)₂ (15 mol equiv) andpiperidine (15 mol equiv) in toluene at 80° C. for 2 h. The sameconditions with 7a gave the desired zinc chlorin Zn-8a; the yield waslow (7%) but a more severe problem was that iodinated chlorin byproductswere occasionally obtained. To avoid use of AgIO₃, we reexamined the useof high-potential quinones such as p-chloranil and DDQ, which areeffective oxidants in the two-step one-flask synthesis of porphyrins(Lindsey, J. S. In The Porphyrin Handbook; Kadish, K. M.; Smith, K. M.;Guilard, R., Eds.; Academic Press: San Diego, Calif. 2000, Vol. 1, pp45-118). We previously attempted to use p-chloranil but the chlorinproduct formed gave an incorrect molecule ion peak upon LD-MS analysis.The use of p-chloranil with the tetrahydrobilene-a gave two covalentchlorin-hydroquinone byproducts in greater yields than that of thedesired chlorin. Quinones of lower potential such as duroquinone in thepresence of additives (e.g., AgTf, AgBF₄) resulted in facile formationof the desired chlorin in yields of 60-70%, but we subsequently foundthat omission of the duroquinone caused no change in the yield. Fromthis result, the oxidation was ascribed to O₂ in air. (It is likely thatthe oxidant in the previous reaction conditions employing AgIO₃ also wasO₂.) This observation ultimately led to the following reactionconditions: AgTf (3 mol equiv), Zn(OAc)₂ (15 mol equiv) and2,2,6,6-tetramethylpiperidine (15 mol equiv) in a solvent exposed toair. The following sections describe the iterative optimization processthat led to these reaction conditions. The cleanliness of thesereactions enabled the yield of chlorin to be determined by UV-visspectroscopy.

We first examined the conversion of 7a into Zn-8a in ten solvents ofdiverse polarity and composition (Table 1). Acetonitrile, THF, and DMFwere the best solvents (˜60% yield) but we focused on acetonitrile andTHF for further studies because of their ease of handling. It isnoteworthy that reagent-grade THF gave a slightly higher yield ofchlorin (Zn-8a) compared to that with distilled THF. TABLE 1^(a) SolventTemp. (° C.) Yield (%)^(b) CH₃CN reflux   60 THF reflux   58 DMF 120° C.  57 1,2-dichloroethane reflux   44 DMSO 120° C.   42 Toluene reflux  39 Ethanol reflux   35 pyridine reflux   34^(c) CHCl₃ reflux   19dioxane reflux   17 methanol reflux  <1^(c)^(a)All reactions were performed under the standard conditions employingthe following components: tetrahydrobilene-a (7a) (10 mM), AgTf (3 molequiv), Zn(OAc)₂ (15 mol equiv), 2,2,6,6-tetramethylpiperidine (15 molequiv) under the specified conditions (solvent, temperature) exposed toair for 4.5 h.^(b)Determined by absorption spectroscopy (ε₆₀₉ = 43,600 M⁻¹cm⁻¹) intoluene.^(c)The long wavelength λ_(max) was at 612 nm.

Four amine bases were examined (Table 2) in THF or acetonitrile. Of the4 amines examined, 2,2,6,6-tetramethylpiperidine gave the best resultsin both acetonitrile and THF (72%, 65%). Piperidine, which was used inthe previous method, gave a low yield. TABLE 2^(a) Yield (%)^(b) BaseTHF CH₃CN 2,2,6,6-tetramethylpiperidine   65 72 triethylamine   35 57piperidine   41^(c) 31 2,5-di-tert-butylpyridine  <1 <1^(a)All reactions were performed under the standard conditions employingthe following components: tetrahydrobilene-a (7a) (10 mM), AgTf (3 molequiv), Zn(OAc)₂ (15 mol equiv), specified base (15 mol equiv) at refluxin the specified solvent exposed to air for 4.5 h.^(b)Determined by absorption spectroscopy (ε₆₀₉ = 43,600 M⁻¹cm⁻¹) intoluene.^(c)The long wavelength λ_(max) was at 612 nm.

We examined the amount of AgTf required for the reaction (Table 3). Whena large excess of AgTf was used, little chlorin Zn-8a was formed. Thebest result was obtained using 2 to 5 mol equiv of AgTf. TABLE 3^(a) Molequiv of AgTf Yield (%)^(b) 1 46 2 60 3 63 5 68 10  7 15 —^(c)^(a)All reactions were performed under the standard conditions employingthe following components: tetrahydrobilene-a (7a) (10 mM), AgTf(specified amount), Zn(OAc)₂ (15 mol equiv),2,2,6,6-tetramethylpiperidine (15 mol equiv) at reflux in CH₃CN exposedto air for 4.5 h.^(b)Determined by absorption spectroscopy (ε₆₀₉ = 43,600 M⁻¹cm⁻¹ intoluene).^(c)The broad bands in the absorption spectrum precluded accurate yielddetermination.

To establish the absolute requirement for each of the reagents in thechlorin-forming reaction, omission experiments were performed (Table 4).In the absence of AgTf, chlorin was formed at only one-half toone-fourth of the normal level. No chlorin was observed in the absenceof zinc acetate, and only a trace was obtained in the absence of2,2,6,6-tetramethylpiperidine. TABLE 4^(a) Yield (%)^(b) Conditions THFCH₃CN No omission (standard conditions) 58 60 Omission of AgTf 15 35Omission of Zn(OAc)₂ — 0 Omission of 2,2,6,6-tetramethylpiperidine — <1^(a)All reactions were performed under the following conditions (withomission of the specified component): tetrahydrobilene-a (7a) (10 mM),AgTf (3 mol equiv), Zn(OAc)₂ (15 mol equiv),2,2,6,6-tetramethylpiperidine (15 mol equiv) at reflux in the specifiedsolvent exposed to air for 4.5 h.^(b)Determined by absorption spectroscopy (ε₆₀₉ = 43,600 M⁻¹cm⁻¹) intoluene.

The concentration dependence of the reaction was examined by performingthe reaction of the tetrahydrobilene-a 7a at 1, 3 or 10 mM and scalingthe concentrations of the reagents linearly. The yield of chlorin wasessentially constant over this 10-fold change in concentration.

The time course of the reaction was monitored by absorptionspectroscopy. The spectral evolution of the oxidation process is shownin FIG. 3. Within one minute, a sharp absorption band is evident at 505nm, which resembles that of a zinc-bis(dipyrrinato) chromophore (Granickand Gilder, In Advances in Enzymology; Nord, F. F. Ed.; Interscience:New York, 1947; Vol. 7, pp 358-363; Johnson, et al. (1959) J. Chem. Soc.3416-3424; Motekaitis and Martell (1970) Inorg. Chem. 9:1832-1839;March, et al. (1971) J. Chem. Soc. (A) 440-448; Murakami, et al. (1973)J. Chem. Soc. Dalton Trans. 1734-1737; Hill and Williamson (1985) J.Chem. Soc., Chem. Commun. 1228-1229; Brückner, et al. (1996) Can. J.Chem. 74:2182-2193) but such an assignment is not certain (see EXAMPLE3). A zinc-dipyrrin could form by chelation of a partially oxidizedproduct of the initial tetrahydrobilene-a. The peak at 505 nm increasedas the reaction proceeded for 35 min and then decreased. The absorptionspectra also show the appearance after 8 min of the characteristicchlorin peaks at 413 and 609 nm, which continue growing in over 1 h.After 1 h, more than 40% of tetrahydrobilene-a 7a had been convertedinto chlorin Zn-8a. The yield of chlorin as a function of time wasreadily assessed based on the intensity of the peak at 609 nm. Theresulting yield versus time plot is shown in FIG. 4. The formation ofthe chlorin Zn-8a is essentially complete within 5 h.

In summary, the conditions for converting the tetrahydrobilene-a intothe chlorin are as follows: tetrahydrobilene-a (10 mM), AgTf (3 to 5 molequiv), Zn(OAc)₂ (15 mol equiv), and 2,2,6,6-tetramethylpiperidine (15mol equiv) in acetonitrile at reflux in air for 4 to 6 h. Theseconditions were applied to a larger-scale synthesis of chlorin Zn-8a.Thus, 75.8 mg of tetrahydrobilene-a 7a was converted to 45 mg of chlorinZn-8a in 62% yield.

One-Flask Procedure for Synthesis of Chlorins. The condensation yieldinga tetrahydrobilene-a and subsequent oxidative cyclization yielding thechlorin has heretofore been implemented in a sequential two-flaskprocedure. The first step is an intermolecular reaction and should notrequire dilute conditions; the second step is an itramolecularcyclization and should proceed in greater yield under dilute conditions.Accordingly, we investigated a one-flask procedure employing 100 mMreactants in the condensation procedure and 10 mM reactants in thecyclization procedure. After condensation of Western Half (4) andEastern half 6a-OH using 100 mM of TFA in acetonitrile, the reactionmixture was diluted 10-fold by addition of CH₃CN. The components for theoxidation were added [AgTf (3 mol equiv), Zn(OAc)₂ (15 mol equiv) and2,2,6,6-tetramethylpiperidine (30 mol equiv rather than 15 equiv, toneutralize the TFA)] and the mixture was refluxed with exposure to air.After 18 h, the reaction mixture was chromatographed, affording chlorinZn-8a in 31% yield (Eq 2). Although this one-flask approach is simpleand readily implemented, the two-flask process affords a higher yield(45%) of chlorin.

Extension to the Synthesis of Meso-Substituted Chlorins. We investigatedthe synthesis of meso-substituted chlorins bearing two types ofsubstituents: (1) strong electron-withdrawing groups and (2) synthetichandles at defined locations at the perimeter of the macrocycle. Theformer establish the scope of the methodology and the latter enableconstruction of chlorin-containing model systems in biomimetic ormaterials chemistry.

The synthesis of meso-substituted Eastern halves follows establishedmethodology for the one-flask synthesis of meso-substituteddipyrromethanes (Littler, et al. (1999) J. Org. Chem. 64(4):1391-1396),monoacylation of a dipyrromethane (Rao, et al. (2000) J. Org. Chem.65(4):1084-1092), and monobromination of a dipyrromethane (Strachan, etal. (2000) J. Org. Chem. 65:3160-3172). The precursors tomeso-substituted Eastern halves 6b-e have been prepared (Scheme 3). Thedipyrromethanes 9b-e (Rao, et al. (2000) J. Org. Chem. 65(4):1084-1092)were treated with ethylmagnesium bromide followed by pyridyl thioesters(10-12)(Strachan, et al. (2000) J. Org Chem. 65:3160-3172; Goto, et al.(1980) Chem. Lett. (1):51-52) affording monoacyldipyrromethanes 13b-e in54-60% yield. Bromination of the latter by treatment with NBS in THF at-78° C. afforded the desired precursor to the Eastern halves 6b-e in65-84% yield.

While all of the tetrahydrobilenes (7a-f) were stable for a period of ≧1month, the Eastern half precursors (1-bromo-9-aroyldipyrromethanes)exhibited a range of stability. Compounds 6a-c or 6d showeddecomposition after a few days or one week, respectively, while 6e and6f were stable for >1 month.

The synthesis of meso-substituted chlorin building blocks was carriedout by the two-flask method as shown in Scheme 4. This route is to becompared with the previous route shown in Scheme 1. In each case, thenew Western half 4 was employed. In these preparative syntheses, theoxidative cyclization process was monitored by absorption spectroscopy,showing the rise and fall of the intermediate (λ_(abs)˜505 nm) and theformation of the chlorin (λ_(abs)˜609 nm). In general the oxidativecyclization was nearly complete at 4-8 h but the reactions were oftencontinued for up to 24 h.

The various meso-substituted chlorins prepared via this method are shownin Chart 1. The synthesis of chlorin Zn-8a provides a benchmark foryield comparisons. The reaction of 4 and 6a-OH afforded tetrahydrobilene7a in 72% yield; oxidative conversion of the latter afforded Zn-8a in62% yield. The reaction of the bis(pentafluorophenyl)-substitutedEastern half with 4 gave the tetrahydrobilene 7b in 32% yield and thechlorin Zn-8b in 38% yield. Several chlorin building blocks wereprepared. The reaction of the Eastern half bearing a TMS-protected ester(6c-OH) with 4 gave the tetrahydrobilene 7c and chlorin Zn-8c inreasonable yields (55%, 41%). An iodo-substituted chlorin (Zn-8d) wasprepared by reaction of the corresponding Eastern half 6d. We attemptedto prepare a chlorin bearing a trimethylsilyl-protected ethyne byreaction of Eastern half 6e. The tetrahydrobilene 7e was formedsmoothly. However, oxidative cyclization afforded the chlorin with theethyne lacking the trimethylsilyl protecting group (Zn-7e). Thesynthesis of a similar trimethylsilyl-protected ethyne chlorin wasattempted with oxidative cyclization of tetrahydrobilene 7f in THFrather than CH₃CN and again the deprotected ethynyl chlorin (Zn-8f) wasobtained. In two cases a comparison was made of the oxidativecyclization in CH₃CN or in THF; in each case (7d, 7e) the yield of zincchlorin was slightly higher in THF. Zinc chlorins Zn-7d and Zn-7e bothincorporate the 3,5-di-tert-butyl group for increased solubility inorganic solvents. In no case was scrambling yielding a mixture ofchlorins detected.

It is noteworthy that in each synthesis the intermediatetetrahydrobilene-a was isolated in substantial quantities (73-460 mg),characterized, and found to be reasonably stable. The yields of chlorinswere 2-4-fold greater than those obtained previously where comparisonscould be made. For example, the prior synthetic method afforded chlorinsZn-8a, Zn-8b, or Zn-8c in yields of 10, 6, or 10% (see Experimental),respectively, to be compared with 45, 12, or 23% in the current method.Note that the deprotected ethynyl chlorin Zn-8f was obtained herein in30% yield, in contrast to the 9% yield of the protected ethynyl chlorinby the previous method. CHART 1

6a-f 7a-f Zn-8a-f Stepwise Yields (%) Total Ar¹ Ar² Tetrahydrobilene 7Chlorin Zn-8 Yield (%) a

72 62 45 b

32 38 12 c

55 41 23 d

40 40 (43) 16 e

59 R = TMS 27 (32) R = H 16 f

66 R = TMS (45) R = H 30(yields in parentheses were obtained in THF rather than CH₃CN)General Experimental Methods.

¹H and ¹³C NMR spectra (300 MHz) were collected in CDCl₃ unless notedotherwise. Absorption spectra were obtained in toluene at roomtemperature. Chlorins were analyzed by laser desorption massspectrometry (LD-MS) in the absence of a matrix (Fenyo, et al. (1997) J.Porphyrins Phthalocyanines 1:93-99; Srinivasan, et al. (1999) J.Porphyrins Phthalocyanines 3:283-291). Fast atom bombardment massspectrometry (FAB-MS) data are reported for the molecule ion orprotonated molecule ion. Pyrrole was distilled at atmospheric pressurefrom CaH₂. Melting points are uncorrected. p-Iodobenzaldehyde wasobtained from Karl Industries, Inc. All other reagents and startingmaterials were obtained from Aldrich. Column chromatography wasperformed with flash silica (Baker). The reduction yielding the Easternhalf was performed following a standard procedure for formingdipyrromethane-carbinols (Rao et al. (2000) J. Org. Chem. 65:1084-1092).

Solvents. THF was distilled from sodium benzophenone ketyl as required.Toluene was distilled from CaH₂. CH₃CN (Fisher certified A.C.S.) for usein the condensation process was distilled from CaH₂ and stored overpowdered molecular sieves. Nitromethane was stored over CaCl₂. Anhydrousmethanol was prepared by drying over CaH₂ for 12 h followed bydistillation. Other solvents were used as received.

Non-commercial compounds. The compounds 2, 6a, 6b, 6f, 10, 12, 13a, 13band 13f were prepared as described in the literature (Strachan, et al.(2000) J. Org. Chem. 65:3160-3172). The compounds 9a-d (Littler, et al.(1999) J. Org Chem. 64:1391-1396) and 9e (Cho, et al. (1999) J. Org.Chem. 64:7890-7901) also were prepared as described in the literature.

1,3,3-Trimethyl-2,3,4,5-tetrahydrodipyrrin N¹⁰-oxide (3). Following ageneral procedure (Battersby, et al. (1984) J. Chem. Soc. Perkin Trans.1 (12):2725-2732), to a vigorously stirred solution of1-(2-pyrrolyl)-2-nitro-3,3-dimethyl-5-hexanone 2 (1.26 g, 5.29 mmol) in25 mL of acetic acid and 25 mL of ethanol at 0° C., zinc dust (8.64 g,132 mmol) was added slowly in small portions for 5 min. The reactionmixture was stirred at 0° C. for 15 min, and then was filtered throughCelite. The filtrate was concentrated under high vacuum. The resultingbrown solid was purified by column chromatography [silica; packed andeluted with ethyl acetate/CH₂Cl₂ (1:1), then eluted with CH₂Cl₂/methanol(9:1)] affording a brown oil that solidified to brownish crystals onstanding at room temperature (943 mg, 86%): mp 85-87° C.; ¹H NMR δ 1.12(s, 3H), 1.17 (s, 3H), 2.04 (s, 3H), 2.28 (d, J=17.6 Hz, 1H), 2.44 (d,J=17.6 Hz, 1H), 2.95-3.10 (m, 2H), 3.82-3.96 (m, 1H), 5.85-5.97 (m, 1H),6.02-6.11 (m, 1H), 6.64-6.72 (m, 1H), 10.50-10.72 (br, 1H); ¹³C NMR δ13.9, 23.4, 26.3, 28.5, 37.8, 47.7, 81.9, 107.0, 107.9, 118.1, 129.2,147.3; FAB-MS obsd 206.1415, calcd 206.1419 (C₁₂H₁₈N₂O).

1,3,3-Trimethyl-2,3,4,5-tetrahydrodipyrrin (4). Following a generalprocedure for the deoxygenation of N-oxides (Malinowski, M. (Aug. 1987)Synthesis-Stuttgart (8):732-734) with slight modification, TiCl₄ (2.87mL, 26.2 mmol) was slowly added to a stirred solution of dry THF (60 mL)under argon at 0° C. To the resulting yellow solution was slowly addedLiAlH₄ (665 mg, 17.5 mmol). The resulting black mixture was stirred atroom temperature for 15 min and then triethylamine (23.0 mL, 164 mmol)was added. The black mixture was then poured into a solution of 3 (725mg, 3.65 mmol) in dry THF (45 mL). The mixture was stirred for 30 min atroom temperature and then water (45 mL) was added. The mixture wasfiltered. The filtrate was extracted with CH₂Cl₂. The organic layer wasdried (Na₂SO₄) and evaporated under reduced pressure. The resultingyellow oil was purified by chromatography (silica, ethyl acetate) togive a pale yellow oil, which solidified to a pale yellow solid oncooling (448 mg, 65%): mp 53-54° C.; ¹H NMR δ 0.94 (s, 3H), 1.10 (s,3H), 2.04 (m, 3H), 2.23-2.42 (m, 2H), 2.54-2.65 (m, 1H), 2.73-2.82 (m,1H), 3.57-3.68 (m, 1H), 5.90-5.97 (m, 1H), 6.05-6.13 (m, 1H), 6.67-6.73(m, 1H), 9.70-9.92 (br, 1H); ¹³C NMR δ20.3, 22.6, 27.0, 27.9, 41.8,54.1, 80.1, 105.1, 107.1, 116.3, 131.4, 174.6; FAB-MS obsd 191.1551,calcd 191.1548 (C₁₂H₁₈N₂).

Byproduct (5). To a vigorously stirred solution of 2 (2.00 g, 8.39 mmol)in 40 mL of acetic acid at room temperature, zinc dust (13.7 g, 210mmol) was added all at once. The reaction mixture was stirred at roomtemperature for 1 h, and then was filtered through Celite. The filtratewas removed under vacuum and CH₂Cl₂ (100 mL) was added. The solution waswashed with 10% aqueous Na₂CO₃ (100 mL). The organic layer was separatedand chromatographed, affording 3 (143 mg, 8.2%). The aqueous layer wasextracted with CH₂Cl₂ (3×100 mL) and the resulting organic layer wasdried (Na₂SO₄) and concentrated to give a dark pink solid which stillcontained about 10% of the N-oxide (720 mg). Recrystallization (CHCl₃)afforded dark pink crystals (254 mg, 13%). mp 145° C.; ¹H NMR δ 0.95 (s,3H), 1.21 (s, 3H), 1.50 (s, 3H), 1.59 (d, J=11.7 Hz, 1H), 1.74 (d,J=11.7 Hz, 1H), 1.83-1.97 (br, 1H), 2.64 (d, J=16.1 Hz, 1H), 2.86 (dd,J=16.1 Hz, 5.1 Hz 1H), 3.36 (d, J=5.1 Hz, 1H), 5.92-5.99 (m, 1H),6.54-6.60 (m, 1H), 7.72-7.92 (br, 1H); ¹³C NMR δ 24.5, 27.3, 28.5, 34.3,42.0, 58.6, 60.6, 65.4, 103.4, 116.0, 123.6, 129.2; FAB-MS obsd191.1553, calcd 191.1548 (C₁₂H₂₀N₂).

Two-flask procedure for chlorin formation using AgIO₃, exemplified forZn(II)-17,18-dihydro-18,18-dimethyl-5-(4-methylphenyl)-10-mesitylporphyrin(Zn-8a). Following a general procedure for chlorin formation (Strachan,et al. (2000) J. Org. Chem. 65:3160-3172; Balasubramanian, et al. (2000)J. Org Chem. 65:7919-7929), to a solution of 6a (138 mg, 0.300 mmol) in10 mL of anhydrous THF/methanol (4:1) was added a 10-fold excess ofNaBH₄ (113 mg, 3.00 mmol). The reaction was monitored by TLC [silica,hexanes/ethyl acetate (5:1)] and upon completion was carefully quenchedwith cold water (50 mL), then extracted with distilled CH₂Cl₁₂ (3×20mL). The combined organic layers were dried (K₂CO₃) and concentratedunder reduced pressure without heating to afford the carbinol 6a-OH. Theresidue was dissolved in 3 mL of anhydrous CH₃CN.1,3,3-trimethyl-2,3,4,5-tetrahydrodipyrrin (4) (56.5 mg, 0.300 mmol) wasadded followed by TFA (23 μL, 0. 30 mmol). The solution was stirred atroom temperature for 30 min. The reaction was quenched with 10% aqueousNaHCO₃ (50 mL) and extracted with distilled CH₂Cl₂ (3×20 mL). Thecombined organic layers were washed with water, dried (Na₂CO₃) andconcentrated in vacuo without heating. The residue was dissolved in 30mL of toluene, to which AgIO₃ (1.27 g, 4.50 mmol), Zn(OAc)₂ (825 mg,4.50 mmol) and piperidine (445 μL, 4.50 mmol) were added. The reactionmixture was heated at 80° C. for 2 h. The reaction mixture wasconcentrated under reduced pressure. Chromatography of the residue[silica, hexanes/CH₂Cl₂ (2:1)] afforded a blue solid (12 mg, 7%).Analytical data are consistent with literature values (Strachan, et al.(2000) J. Org. Chem. 65:3160-3172).

Studies of the Western Half (4)+Eastern Half (6a-OH) Condensation. Asample of 6a (58.5 mg, 100 μmol) was reduced with NaBH₄ (37.8 mg, 1.00mmol) in 2 mL of anhydrous THF/methanol (4:1). The resulting 6a-OH and 4(18.8 mg, 100 μmol) were dissolved in 10 mL of anhydrous CH₂Cl₂, then 1mL portions of the solution were placed in each of 10 vials (each vialcontains 10 μmol of 6a-OH and 4). The solvent was evaporated and then0.1 mL of CH₃CN containing the desired TFA concentration (10 to 316 mM)was added. After the desired reaction time (1 min to 2h), the solutionwas diluted with 0.9 mL of CH₃CN [containing AgTf (7.7 mg, 30 μmol) and2,2,6,6-tetramethylpiperidine (25.3 μL, 150 μmol)]. Then Zn(OAc)₂ (27.5mg, 150 μmol) was added and the mixture was refluxed for 4.5 h. Thereaction yield was determined by UV-vis spectroscopy. In the yielddeterminations, CH₃CN was added to each reaction mixture to bring thevolume to 4.0 mL (thereby negating any possible error due to solventevaporation during the reflux period). A 25 μL aliquot was then removedand transferred to a 4 mL cuvette (containing toluene). Quantitation wasthen based on the absorption at 609 nm (ε₆₀₉=43,600 M⁻¹cm⁻¹).

1,3,3-Trimethyl-10-(4-methylphenyl)-15-mesityl-19-bromo-2,3,4,5-tetrahydrobilene-a (7a). Following a general procedure, treatmentof 6a (585 mg, 1.00 mmol) with NaBH4 (370 mg, 10.0 mmol) in 20 mL ofanhydrous THF/methanol (4:1) afforded 6a-OH. The sample of 6a-OH wasdissolved in 10 mL of anhydrous CH₃CN, then 4 (188 mg, 1.00 mmol) andTFA (77 μL, 1.0 mmol) were added. The reaction mixture was stirred atroom temperature for 30 min. Then 10% aqueous NaHCO₃ (50 mL) was addedand the mixture was extracted with distilled CH₂Cl₂ (3×20 mL). Thecombined organic layers were washed with water, dried (Na₂CO₃) andconcentrated in vacuo without heating. The resulting brown solid waspurified by chromatography [silica, hexanes/ethyl acetate (5:1), andthen ethyl acetate] to give a brown solid (460 mg, 72%): mp 67-70° C.;¹H NMR δ 0.90 (s, 3H), 1.07 (s, 3H), 1.91 (s, 3H), 2.04 (s, 6H), 2.25(s, 3H), 2.26-2.30 (m, 2H), 2.31 (s, 3H), 2.48-2.60 (m, 1H), 2.66-2.72(m, 1H), 3.52-3.63 (m, 1H), 5.28-5.32 (m, 1H), 5.67-5.81 (m, 6H),6.00-6.04 (m, 1H), 6.81 (s, 1H), 7.06-7.11 (m, 4H), 7.67-7.79 (br, 1H),7.99-8.13 (br, 1H), 9.23-9.32 (br, 1H); FAB-MS obsd 635.2749, calcd635.2730 (C₃₈H₄₃BrN₄).

Studies of the Metal-Mediated Oxidative Cyclization. A solution oftetrahydrobilene 7a (63.5 mg, 100 μmol) in 10 mL of anhydrous CH₂Cl₂ wasdivided into 0.5 mL portions in each of 20 vials (each vial contains 5μmol of 7a). For the study examining the effect of the reaction solvent,CH₂Cl₂ was then evaporated, and 0.5 mL of the solvent of interest wasadded. The corresponding reagents for the oxidation[2,2,6,6-tetramethylpiperidine (13 μL, 77 μmol) and Zn(OAc)₂ (14 mg, 76μmol)] were added and the mixture was refluxed for 4.5 h. The yield ofchlorin was determined by UV-vis spectroscopy. In the yielddeterminations, CH₂Cl₂ was added to each reaction mixture to bring thevolume to 4.0 mL (thereby negating any possible error due to solventevaporation during the reflux period). A 50 μL aliquot was then removedand transferred to a 4 mL cuvette (containing toluene). Quantitation wasthen based on the absorption at 609 nm (ε₆₀₉=43,600 M⁻¹cm⁻¹).

Two-flask procedure for chlorin formation, exemplified forZn(II)-17,18-dihydro-18,18-dimethyl-5-(4-methylphenyl)-10-mesitylporphyrin(Zn-8a). A solution of 7a (75.8 mg, 0.120 mmol) in CH₃CN (12 mL) wastreated with Zn(OAc)₂ (328 mg, 1.79 mmol), AgTf (91.9 mg, 0.360 mmol)and 2,2,6,6-tetramethylpiperidine (300 μL, 1.79-mmol). The reactionmixture was refluxed for 24 h. The reaction mixture was concentratedunder reduced pressure, and then the residue was chromatographed[silica, hexanes/CH₂Cl₂ (2:1)] to give a blue solid (45 mg, 62%).Analytical data are consistent with literature values (Strachan, et al.(2000) J. Org. Chem. 65:3160-3172).

One-flask procedure for chlorin formation, exemplified forZn(II)-17,18-dihydro-18,18-dimethyl-5-(4-methylphenyl)-10-mesitylporphyrin(Zn-8a). Following a general procedure, treatment of 6a (231mg,0.500mmol) with NaBH₄ (185 mg, 5.00 mmol) in 20 mL of anhydrousTHF/methanol (4:1) afforded 6a-OH. The sample of 6a-OH was dissolved in5 mL of anhydrous CH₃CN, then 4 (94 mg, 0.50 mmol) and TFA (39 μL, 0.50mmol) were added. The reaction mixture was stirred at room temperaturefor 30 min, then the reaction mixture was diluted with 45 mL of CH₃CN.AgTf (385 mg, 1.50 mmol), Zn(OAc)₂ (1.38 g, 7.50 mmol) and2,2,6,6-tetramethylpiperidine (2.53 mL, 15.0 mmol, 30 mol equiv) wereadded. The resulting mixture was refluxed for 18 h. The reaction mixturewas concentrated under reduced pressure. The residue was chromatographed[silica, hexanes/CH₂Cl₂ (2:1)], affording a blue solid (118 mg, 31%).Analytical data are consistent with literature values (Strachan, et al.(2000) J. Org. Chem. 65:3160-34172).

S-2-Pyridyl 3,5-di-tert-butylbenzothioate (11). To a stirred solution of2-mercaptopyridine (2.78 g, 25.0 mmol) in CH₂Cl₂ (50 mL) was added asolution of 3,5-di-tert-butylbenzoyl chloride (6.31 g, 25.0 mmol) inCH₂Cl₂ (125 mL) over 10 min. After 5 h, TLC showed complete consumptionof the 2-mercaptopyridine, then 2 N NaOH was added. The organic phasewas isolated, washed with water, then dried (Na₂SO₄) and the solvent wasremoved to afford a white solid. The solid was recrystallized in hexaneaffording a white solid (5.05 g, 62%): mp 73-74° C.; ¹H NMR δ 1.36 (s,18H), 7.31-7.36 (m, 1H), 7.67-7.70 (m, 1H), 7.75-7.80 (m, 2H), 7.85-7.88(m, 2H), 8.66-8.69 (m, 1H); ¹³C NMR δ 32.0, 35.7, 122.6, 124.2, 128.9,131.4, 136.9, 137.7, 151.1, 152.3, 152.5, 190.8; Anal. Calcd forC₂₀H₂₅NOS: C, 73.35; H, 7.69; N, 4.28. Found: C, 73.40; H, 7.75; N,4.23.

1-(4-Methylbenzoyl)-5-{4-[2-(trimethylsilyl)ethoxycarbonyl]phenyl}dipyrromethane(13c). Following the general procedure (Rao, et al. (2000) J. Org. Chem.65:1084-1092), EtMgBr (13.1 mL, 13.1 mmol), 1.0 M in THF) was added to asolution of 9c (2.00 g, 5.46 mmol) in dry THF (10 mL) at roomtemperature under argon. The mixture was stirred at room temperature for10 min and then cooled to −78° C. A solution of S-2-pyridyl4-methylbenzothioate (10) (1.25 g, 5.45 mmol) in dry THF (10 mL) wasadded. The reaction mixture was maintained at −78° C. for 10 min, thenthe cooling bath was removed. After 3 h, the reaction was quenched with100 mL of saturated aqueous NH₄Cl. The reaction mixture was extractedwith CH₂Cl₂, washed with water, and then dried (Na₂SO₄) and concentratedunder reduced pressure to give a dark foam. Column chromatography[silica packed with hexanes/ethyl acetate (10:1), eluted withhexanes/ethyl acetate (5:1)] afforded a golden amorphous solid (1.42 g,54%): mp 67-70° C.; ¹H NMR δ 0.07 (s, 9H), 1.11 (t, J=8.1 Hz, 2H), 2.42(s, 3H), 4.39 (t, J=8.1 Hz, 2H), 5.62 (s, 1H), 5.95-5.99 (m, 1H),6.06-6.10 (m, 1H), 6.12-6.16 (m, 1H), 6.64-6.68 (m, 1H), 6.77-6.81 (m,1H), 7.16-7.30 (m, 4H), 7.67 (d, J=7.3 Hz, 2H), 7.89 (d, J=7.3 Hz, 2H),8.52-8.68 (br, 1H), 10.30-10.42 (br, 1H); ¹³C NMR δ -0.8, 18.0, 22.2,44.6, 63.9, 108.6, 109.0, 111.3, 118.7, 121.4, 128.9, 129.6, 129.7,130.1, 130.4,. 130.8, 131.6, 136.1, 141.4, 143.1, 146.5, 167.1, 185.3;Anal. Calcd for C₂₉H₃₂N₂O₃Si: C, 71.87; H, 6.65; N, 5.78. Found: C,71.78; H, 6.61; N, 5.89.

1-(3,5-Di-tert-butylbenzoyl)-5-(4-iodophenyl)dipyrromethane (13d).Following the general procedure (Rao, et al. (2000) J. Org. Chem.65(4):1084-1092), reaction of 9d (1.80 g, 5.10 mmol) and 11 (1.70 g,5.10 mmol) followed by column chromatography [silica hexanes/ethylacetate (5:1)] afforded a golden amorphous solid (1.63 g, 56%): mp119-120° C.; ¹H NMR δ 1.34 (s, 18H), 5.51 (s, 1H), 5.93-5.97 (m, 1H),6.07-6.14 (m, 2H), 6.57-6.63 (m, 1H), 6.73-6.77 (m, 1H), 6.92 (d, J=8.1Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.60-7.67 (m, 3H), 8.57-8.70 (br, 1H),10.38-10.52 (br, 1H); ¹³C NMR δ 32.1, 35.6, 44.4, 93.3, 108.1, 108.5,109.1, 111.3, 118.1, 118.8, 121.8, 124.1, 126.7, 130.9, 131.9, 138.3,141.4, 141.8, 151.5, 186.6; Anal. Calcd for C₃₀H₃₃IN₂O: C, 63.83; H,5.89; N, 4.96. Found: C, 63.59; H, 5.95; N, 4.83.

1-(3,5-Di-tert-butylbenzoyl)-5-{4-[2-(trimethylsilyl)ethynyl]phenyl}dipyrromethane(13e). Following the general procedure (Rao, et al. (2000) J. Org. Chem.65(4):1084-1092), reaction of 9e (2.00 g, 6.28 mmol) and 11 (2.06 g,6.28 mmol) followed by column chromatography [silica hexanes/ethylacetate (5:1)] afforded a golden amorphous solid (2.00 g, 60%): mp 108°C. (dec.) ¹H NMR δ0.23 (s, 9H), 1.34 (s, 18H), 5.57 (s, 1H), 5.93-5.97(m, 1H), 6.06-6.16 (m, 2H), 6.58-6.62 (m, 1H), 6.75-6.80 (m, 1H), 7.10(d, J=8.1 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 7.60-7.68 (m, 3H), 8.62-8.70(br, 1H), 10.45-10.52 (br, 1H); ¹³C NMR δ0.7, 32.1, 35.6, 44.7, 94.9,105.6, 108.4, 108.9, 111.4, 118.8, 122.1, 122.5, 124.2, 126.7, 128.9,131.3, 131.8, 132.8, 138.4, 142.1, 142.4, 151.5, 186.8; Anal. Calcd forC₃₅H₄₂N₂OSi: C, 78.60; H, 7.92; N, 5.24. Found: C, 78.75; H, 7.96; N,5.20.

1-Bromo-9-(4-methylbenzoyl)-5-{4-[2-(trimethylsilyl)ethoxycarbonyl]phenyl}dipyrromethane(6c). Following the general procedure (Strachan, et al. (2000) J. Org.Chem. 65:3160-3172; Balasubramanian, et al. (2000) J. Org. Chem.65:7919-7929), a solution of 13c (470 mg, 0.970 mmol) in 25 mL of dryTHF was cooled to −78° C. under argon. NBS (173 mg, 0.970 mmol) wasadded, and the reaction mixture was stirred for 1 h at −78° C. Hexanes(50 mL) and water (50 mL) were added and the mixture was allowed to warmto room temperature. The organic phase was extracted with CH₂Cl₂ anddried (Na₂SO₄) and the solvent was removed under reduced pressurewithout heating. Column chromatography [silica; hexanes/ethyl acetate(4:1)] afforded a light brown powder (444 mg, 81%): mp 152° C. (dec.);¹H NMR δ 0.07 (s, 9H), 1.11 (t, J=8.1 Hz, 2H), 2.16 (s, 3H), 4.39 (t,J=8.1 Hz, 2H), 5.57 (s, 1H), 5.89-5.93 (m, 1H), 6.02-6.06 (m, 1H),6.09-6.13 (m, 1H), 6.76-6.80 (m, 1H), 7.17 (d, J=8.1 Hz, 2H), 7.23 (d,J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.1 Hz, 2H), 9.10-9.26(br, 1H), 10.82-10.94 (br, 1H); ¹³C NMR δ −0.9, 17.9, 22.2, 44.6, 63.8,98.8, 105.0, 110.4, 110.8, 111.2, 122.1, 128.7, 129.5, 129.8, 130.1,130.3, 131.7, 132.4, 141.2, 143.2, 145.9, 167.0, 185.7; Anal. Calcd forC₂₉H₃₁BrN₂O₃Si: C, 61.81; H, 5.54; N, 4.97. Found: C, 61.96; H, 5.53; N,4.93.

1-Bromo-9-(3,5-di-tert-butylbenzoyl)-5-(4-iodophenyl)dipyrromethane(6d). Following the general procedure outlined for the synthesis of 6c,reaction of 13d (800 mg, 1.42 mmol) with NBS (253 mg, 1.42 mmol)followed by-column chromatography [silica hexanes/ethyl acetate (4:1)]afforded a light brown powder (770 mg, 84%): mp 88-91° C.; ¹H NMR δ 1.34(s, 18H), 5.51 (s, 1H), 5.89 (t, J=2.9 Hz, 1H), 6.03 (t, J=2.9Hz, 1H),6.11 (t, J=2.9 Hz, 1H), 6.77 (t, J=2.9 Hz, 1H), 6.96 (d,J=8.1 Hz, 2H),7.51 (d, J=8.1 Hz, 2H), 7.62 (s, 3H), 8.91-9.00 (br, 1H), 10.59-10.72(br, 1H); ¹³C NMR δ 32.1, 35.6, 44.5, 93.5, 98.8, 110.4, 111.1, 111.4,122.2, 124.2, 126.9, 130.9, 132.0, 132.6, 138.2, 138.4, 140.7, 141.3,151.6, 187.0; Anal. Calcd for C₃₀H₃₂BrIN₂O: C, 56.00; H, 5.01; N, 4.35.Found: C, 56.15; H, 5.19; N, 4.22.

1-Bromo-9-(3,5-di-tert-butylbenzoyl)-5-{4-[2-(trimethylsilyl)ethynyl]phenyl}dipyrromethane(6e). Following the general procedure outlined for the synthesis of 6c,reaction of 13e (1.00 g, 1.87 mmol) with NBS (333 mg, 1.87 mmol)followed by column chromatography [silica hexanes/ethyl acetate (5:1)]afforded a golden amorphous solid (914 mg, 80%): mp 118° C. (dec.); ¹HNMR δ 0.23 (s, 9H), 1.33 (s, 18H), 5.56 (s, 1H), 5.86-5.91 (m, 1H),6.01-6.04 (m, 1H), 6.08-6.12 (m, 1H), 6.74-6.79 (m, 1H), 7.15 (d, J=8.1Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.58-7.67 (m, 3H), 8.94-9.06 (br, 1H),10.62-10.76 (br, 1H); ¹³C NMR δ 0.6, 32.1, 35.6, 44.8, 95.3, 98.7,105.3, 110.3, 111.1, 111.4, 122.0, 122.8, 124.2, 126.7, 128.8, 131.9,132.7, 132.9, 138.3, 141.2, 141.3, 151.5, 186.9; Anal. Calcd forC₃₅H₄₁BrN₂OSi: C, 68.50; H, 6.73; N, 4.56. Found: C, 68.48; H, 6.87; N,4.47.

1,3,3-Trimethyl-10,15-bis(pentafluorophenyl)-19-bromo-2,3,4,5-tetrahydrobilene-a(7b). Following the general procedure, treatment of 6b (176 mg, 0.300mmol) with NaBH4 (113 mg, 3.00 mmol) in 10 mL of anhydrous THF/methanol(4:1) afforded 6b-OH. The reaction of 6b-OH and 4 (57 mg, 0.30 mmol) in3 mL of anhydrous CH₃CN containing TFA (23 μL, 0.30 mmol) for 30 minfollowed by the standard workup afforded a brown solid (73 mg, 32%): mp56-58° C.; ¹H NMR δ 0.90 (s, 3H), 1.11 (s, 3H), 1.92 (s, 3H), 2.23-2.42(m, 2H), 2.50-2.72 (m, 2H), 3.52-3.62 (m, 1H), 5.73-6.08 (m, 8H),8.27-8.46 (br, 1H), 8.58-8.70 (br, 1H), 9.72-9.85 (br, 1H); Anal. Calcdfor C₃₄H₂₅BrF₁₀N₄: C, 53.77; H; 3.32; N, 7.38. Found: C, 53.51; H, 3.41;N, 6.97; FAB-MS obsd 759.1181, calcd 759.1215 (C₃₄H₂₅BrF₁₀N₄).

Zn(II)-17,18-Dihydro-18,18-dimethyl-5,10-bis(pentafluorophenyl)porphyrin(Zn-8b). A solution of 7b (77.7 mg, 0.102 mmol) in CH₃CN (10 mL)containing the oxidative cyclization reagents was refluxed for 24 h.Standard workup and chromatography [silica, hexanes/CH₂Cl₂ (2:1)] gave agreenish blue solid (28.2 mg, 38%). Analytical data are consistent withliterature values (Strachan, et al. (2000) J. Org. Chem. 65:3160-3172).

1,3,3-Trimethyl-10-(4-methylphenyl)-15-{4-[2-(trimethylsilyl)ethoxycarbonyl]phenyl}-19-bromo-2,3,4,5-tetrahydrobilene-a(7c). Following the general procedure, treatment of 6c (282 mg, 0.500mmol) with NaBH₄ (189 mg, 5.00 mmol) in 30 mL of anhydrous THF/methanol(4:1) afforded 6c-OH. The reaction of 6c-OH and-4 (94 mg, 0.50 mmol) in5 mL of anhydrous CH₃CN with TFA (39 μL, 0.50 mmol) for 30 min followedby the standard workup afforded a brown solid (203 mg, 55%): mp 81-83°C.; ¹H NMR δ 0.14 (s, 9H), 0.96 (s, 3H), 1.14 (s, 3H), -1.15 (t, J=8.1Hz, 2H), 1.92-1.97 (m, 3H), 2.24-2.43 (m, 2H), 2.38 (s, 3H), 2.53-2.67(m, 1H), 2.71-2.80 (m, 1H), 3.57-3.68 (m, 1H), 4.47 (t, J=8.1 Hz, 2H),5.32-5.43 (m, 2H), 5.72-5.84 (m, 4H), 5.84-5.90 (m, 1H), 6.05-6.10 (m,1H), 7.10-7.18 (m, 4H), 7.24-7.34 (m, 2H), 7.90-8.06 (m, 1H), 7.96-8.04(m, 2H), 8.21-8.46 (m, 1H), 9.23-9.36 (m, 1H); FAB-MS obsd 737.2907,calcd 737.2886 (C₄₁H₄₉BrN₄O₂Si).

Zn(II)-17,18-Dihydro-18,18-dimethyl-5-(4-methylphenyl)-10-[4-[2-(trimethylsilyl)ethoxycarbonyl]phenyl]porphyrin(Zn-8c). A solution of 7c (110 mg, 0.150 mmol) in CH₃CN (15 mL)containing the oxidative cyclization reagents was refluxed for 14 h.Standard workup and chromatography [silica, hexanes/CH₂Cl₂ (1:2)] gave ablue solid (43 mg, 41%): ¹H NMR δ 0.18 (s, 9H), 1.12 (t, J=5.5 Hz, 2H),2.03 (s, 6H), 2.66 (s, 3H), 4.52 (s, 2H), 4.65 (t, J=5.5 Hz, 2H), 7.48(d, J=8.1 Hz, 2H), 7.94 (d, J=8.1 Hz, 2H), 8.13 (d, J=8.1 Hz, 2H), 8.31(d, J=4.4 Hz, 1H), 8.34 (d, J=8.1 Hz, 2H), 8.42 (d, J=4.4 Hz, 1H),8.57-8.70 (m, 6H); LD-MS obsd 710.78; FAB-MS obsd 712.2232, calcd712.2212 (C₄₁H₄₀N₄O₂SiZn); λ_(abs) (toluene) 413, 609 nm.

1,3,3-Trimethyl-10-(3,5-di-tert-butylphenyl)-15-(4-iodophenyl)-19-bromo-2,3,4,5-tetrahydrobilene-a(7d). Following the procedure, treatment of 6d (322 mg, 0.500 mmol) withNaBH₄ (189 mg, 5.00 mmol) in 30 mL of anhydrous THF/methanol (4:1)afforded 6d-OH. The reaction of 6d-OH and 4 (94 mg, 0.50 mmol) in 5 mLof anhydrous CH₃CN containing TFA (39 μL, 0.50 mmol) followed bystandard workup afforded a brown solid (163 mg, 40%): mp 70-73° C.; ¹HNMR δ 0.91 (s, 3H), 1.06 (s, 3H), 1.25 (s, 18H), 1.83-1.87 (m, 3H),2.17-2.34 (m, 2 H), 2.51-2.62 (m, 1H), 2.66-2.76 (m, 1H), 3.52-3.59 (m,1H), 5.22-5.27 (m, 1H), 5.29-5.35 (m, 1H), 5.66-5.88 (m, 5H), 5.97-6.03(m, 1H), 6.87-6.93 (m, 2H), 7.00-7.07 (m, 3H), 7.54-7.62 (m, 2H),7.79-7.94 (m, 1H), 8.08-8.28 (m, 1H), 9.08-9.22 (m, 1H), Anal. Calcd forC₄₂H₅₀BrIN₄: C, 61.69; H, 6.16; N, 6.85. Found: C, 61.57; H, 6.21; N,6.70; FAB-MS obsd 81i.2317, calcd 817.2342 (C₄₂H₅₀BrIN₄).

Zn(II)-17,18-Dihydro-18,18-dimethyl-5-(3,5-di-tert-butylphenyl)-10-(4-iodophenyl)porphyrin(Zn-8d). A solution of 7d (81.7 mg, 0.100 mmol) in CH₃CN (10 mL)containing the oxidative cyclization reagents was refluxed for 20 h.Standard workup and chromatography [silica, hexanes/CH₂Cl₂ (1:2)] gave ablue solid (32 mg, 40%): ¹H NMR δ 1.49 (s, 18H), 2.03 (s, 6H), 4.51 (s,2H), 7.72 (t, J=1.5 Hz, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.89-7.93 (m, 2H),8.01 (d, J=8.1 Hz, 2H), 8.35 (d, J=4.5 Hz, 1H), 8.44 (d, J=4.5 Hz, 1H),8.58 (s, 1H), 8.61-8.63 (m, 2H), 8.65-8.69 (m, 2H), 8.70-8.74 (m, 1H);LD-MS obsd 791.60; FAB-MS obsd 792.1667, calcd 792.1689 (C₄₂H₄₁IN₄Zn);λ_(abs) (toluene) 412, 609 nm.

1,3,3-Trimethyl-10-(3,5-di-tert-butylphenyl)-15-{4-[2-(trimethylsilyl)ethynyl]phenyl}-19-bromo-2,3,4,5-tetrahydrobilene-a(7e). Following the general procedure, treatment of 6e (307 mg, 0.500mmol) with NaBH₄ (189 mg, 5.00 mmol) in 30 mL of anhydrous THF/methanol(4:1) afforded 6e-OH. The reaction of 6e-OH and 4 (94 mg, 0.50 mmol) in5 mL of anhydrous CH₃CN containing TFA (39 μL, 0.50 mmol) followed bythe standard workup afforded a brown solid (233 mg, 59%): mp 61-63° C.;¹H NMR δ 0.24 (s, 9H), 0.90 (s, 3H), 1.06 (s, 3H), 1.25 (s, 18H),1.83-1.90 (m, 3H), 2.21-2.47 (m, 2H), 2.49-2.62 (m, 1H), 2.66-2.75 (m,1H), 3.51-3.60 (m, 1H), 5.25-5.3₅ (m, 2H), 5.65-5.88 (m, 5H), 5.96-6.02(m, 1H), 6.97-7.04 (m, 3H), 7.04-7.14 (m, 2H), 7.32-7.42 (m, 2H),7.81-7.96 (m, 1H), 8.07-8.21 (m, 1H), 9.08-9.20 (m, 1H); FAB-MS obsd787.3802, calcd 787.3771 (C₄₇H₅₉BrN₄Si).

Zn(II)-17,18-dihydro-18,18-dimethyl-5-(3,5-di-tert-butylphenyl)-10-(4-ethynyl]phenyl)porphyrin(Zn-8e). A solution of 7e (118 mg, 0.150 mmol) in CH₃CN (15 mL)containing the oxidative cyclization reagents was refluxed for 12 h.Standard workup and chromatography [silica, hexanes/CH₂Cl₂ (2:1)] gave ablue solid (28 mg, 27%). Deprotection of the trimethylsilylethyneapparently occurred under these conditions: ¹H NMR δ 1.49 (s, 18H), 2.02(s, 6H), 3.26 (s, 1H), 4.50 (s, 2H), 7.71-7.74 (m, 1H), 7.81 (d, J=8.1Hz, 2H), 7.90-7.94 (m, 2H), 8.03 (d, J=8.1 Hz, 2H), 8.35 (d, J=4.5 Hz,1H), 8.45 (d, J=4.5 Hz, 1H), 8.58 (s, 1H), 8.59-8.62 (m, 2H), 8.63-8.68(m, 2H), 8.72 (d, J=4.5 Hz, 1H); LD-MS obsd 689.45; FAB-MS obsd690.2748, calcd 690.2701 (C₄₄H₄₂N₄Zn); λ_(abs) (toluene) 413, 609 nm.

1,3,3-Trimethyl-10-(4-methylphenyl)-15-{4-[2-(trimethylsilyl)ethynyl]phenyl}-19-bromo-2,3,4,5-tetrahydrobilene-a(7f). Treatment of 6f (309 mg, 0.600 mmol) with NaBH4 (226 mg, 6.00mmol) in 40 mL of anhydrous THF/methanol (4:1) afforded 6f-OH. Thereaction of 6f-OH and 4 (113 mg, 0.600 mmol) in 6 mL of anhydrous CH₃CNcontaining TFA (46 μL, 0.60 mmol) followed by the standard workupafforded a brown solid (273 mg, 66%): mp 77-79° C.; ¹H NMR δ 0.27 (s,9H), 0.90 (s, 3H), 1.08 (s, 3H), 1.85 (s, 3H), 2.27-2.31 (m, 2H), 2.32(s, 3H), 2.49-2.57 (m, 1H), 2.66-2.71 (m, 1H), 3.52-3.56 (m, 1H),5.23-5.27 (m, 2H), 5.68-5.72 (m, 4H), 5.80-5.84 (m, 1H), 5.99-6.03 (m,1H), 7.05-7.07 (m, 2H), 7.07-7.10 (m, 4H), 7.35-7.39 (m, 2H), 7.84-7.96(m, 1H), 8.16-8.37 (m, 1H), 9.16-9.28 (m, 1H); Anal. Calcd forC₄₀H₄₅BrN₄Si: C, 69.65; H, 6.58; N, 8.12. Found: C, 69.17; H, 6.69; N,7.74; FAB-MS obsd 689.2713, calcd 689.2675 (C₄₀H₄₅BrN₄Si).

Zn(II)-17,18-Dihydro-18,18-dimethyl-5-(4-methylphenyl)-10-(4-ethynyl]phenyl)porphyrin(Zn-8fi. A solution of 7f (158 mg, 0.229 mmol) in THF (23 mL) containingthe oxidative cyclization reagents was refluxed for 24 h. Standardworkup and chromatography [silica, hexanes/CH₂Cl₂ (2:1)] gave a greenishblue solid (61 mg, 45%). Deprotection of the trimethylsilylethyneapparently occurred under these conditions: ¹H NMR δ 2.03 (s, 6H), 2.66(s, 3H), 3.27 (s, 1H), 4.51 (s, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.81 (d,J=8.1 Hz, 2H), 7.94 (d, J=8.1 Hz, 2H), 8.03 (d, J=8.1 Hz, 2H), 8.34 (d,J=4.5 Hz, 1H), 8.41 (d, J=4.5 Hz, 1H), 8.58 (s, 1H), 8.60-8.64 (m, 2H),8.65 (d, J=4.5 Hz, 1H), 8.66 (s, 1H), 8.69 (d, J=4.5 Hz, 1H); LD-MS obsd591.68; FAB-MS obsd 592.1620, calcd 592.1605 (C₃₇H₂₈N₄Zn); λ_(abs) 413,609 nm.

Conclusions. We have refined a number of steps in the synthesis ofmeso-substituted chlorin building blocks. The prior synthesisestablished a general route to chlorins with defined patterns offunctional group handles at the perimeter of the macrocycle. Theweaknesses of the prior synthesis included (1) yields of chlorin in the6-24% range and amounts of chlorin typically in the 5-20 mg range; (2)very short shelf life of the Western half (a dihydrodipyrrin); (3)inability to isolate; characterize, or quantitate the putativedihydrobilene-a intermediate; (4) the use of AgIO₃ in the oxidationmethod which upon prolonged exposure to the reaction mixture resulted iniodinated chlorin byproducts. The refined method described hereinaffords a stable Western half (a tetrahydrodipyrrin) in good yield. TheWestern half undergoes smooth condensation with the Eastern half,affording a stable tetrahydrobilene-a intermediate. Studies of theconversion of the latter to the chlorin revealed simple reactionconditions [AgTf, Zn(OAc)₂, and 2,2,6,6,-tetramethylpiperidine in CH₃CNat reflux exposed to air] that proceed in a clean manner and in goodyield. A one-flask synthetic procedure for chlorin formation has beendeveloped. Using the two-flask procedure, several zinc chlorins weresynthesized in yields of 16-45% (based on the Eastern and Western halfprecursors) and in quantities of 27-118 mg. The isolation of theintermediate tetrahydrobilene-a in each case enabled determination ofthe yield of the condensation of Eastern and Western halves as well asof the oxidative cyclization of the tetrahydrobilene-a yielding the zincchlorin.

EXAMPLE 2.

Refined Synthesis of β-Substituted Chlorin Building Blocks

In this Example, we have employed this refined route to prepare aβ-substituted chlorin that bears an ethyne group and an iodo group indiametrically substituted positions, as well as a 3,5-di-tert-butylgroup at one meso position to impart increased solubility in organicsolvents. This building block is ideally suited for use in the synthesisof linear multi-chlorin arrays analogous to our multi-porphyrin basedmolecular wires (Wagner and Lindsey (1994) J. Am. Chem. Soc.116:9759-9760). The synthesis of such trans-β-substituted chlorinbuilding blocks requires the synthesis of β-substituted Eastern andWestern halves.

Synthesis of Substituted Tetrahydrodipyrrin Western Halves. A criticalstep in the synthesis of the unsubstituted tetrahydrodipyrrin Westernhalf (4) is the deoxygenation of the N-oxide. A Western half bearing asynthetic handle at the β-position provides a convenient entry intoβ-substituted chlorins (Balasubramanian, et al. (2000) J. Org. Chem.65:7919-7929). We recently developed a route to a β-substituteddihydrodipyrrin Western half (Balasubramanian, et al. (2000) J. Org.Chem. 65:7919-7929), which was used herein with modification to obtainthe β-substituted tetrahydrodipyrrin counterpart. The requisiteiodophenyl-substituted nitro-hexanone pyrrole 14 was readily preparedfrom 3-(4-iodophenyl)pyrrole. Subsequent formylation affords twoproducts due to substitution at either the α- or α′-position; adistinction between the two products is essential because the twopatterns of substitution ultimately yield chlorin building blocks withsubstitution at different β-positions. Such distinction is difficult by¹H NMR spectroscopy (Balasubramanian, et al. (2000) J. Org. Chem.65:7919-7929). The remainder of the synthesis of 14 proceeds as for thatof 1 (aldol condensation with nitromethane, reduction with NaBH4,Michael addition with mesityl oxide). Reductive cyclization of 14 in thepresence of Zn/AcOH gave the N-oxide 15 in 43% yield (Scheme 5). AnX-ray structure obtained of 15 confirmed the substitution pattern,thereby eliminating any ambiguity concerning the NMR interpretation ofthe formylated pyrrole precursor (EXAMPLE 3). This structure alsoconfirms the assigned substitution pattern of the dipyrromethanederivatives that serve as the Eastern half, because the same formylatedpyrrole precursor to 14 is employed to prepare the β-substituted Easternhalf (vide infra). Deoxygenation of the N-oxide: 15 yielded theβ-substituted tetrahydrodipyrrin Western half 16 in 38% yield (Scheme5). Sonogashira coupling of 16 with (trimethylsilyl)acetylene affordedthe trimethylsilylethynyl substituted Western half 17 in 76% yield.

Synthesis of Eastern Halves. The synthesis of the β-substituted Easternhalf began in the same manner as our prior synthesis of β-substituteddipyrromethanes (Balasubramanian and Lindsey (1999) Tetrahedron55:6771-6784). A BOC-protected dipyrromethane (18) was obtained from2-formyl-3-(4-iodophenyl)pyrrole through the protection of the pyrrolicnitrogen, reduction of the aldehyde and condensation with pyrrole.Treatment of BOC-protected dipyrromethane with 3.0 equiv of EtMgBr inTHF followed by 3,5-di-tert-butylbenzoyl chloride afforded themonoacylated dipyrromethane 19 in 45% yield (Scheme 6). In thisacylation step, we employed 3,5-di-tert-butylbenzoyl chloride instead ofp-toluoyl chloride to improve the solubility of the resulting chlorin inorganic solvents. Removal of the BOC group under standard conditions(Hasun, et al. (1981) J. Org. Chem. 46:157-164) gave3-(4-iodophenyl)-9-(3,5-di-tert-butylbenzoyl)dipyrromethane (20).Sonogashira coupling (Sonogashira, et al. (1975) Tetrahedron Lett.(50):4467-4470) of 20 with (trimethylsilyl)acetylene affordedtrimethylsilylethynyl dipyrromethane 21 in 82% yield. Reaction of 21with NBS at −78° C. gave the corresponding monobromo monoacyldipyrromethane 22 in 72% yield. Compound 22 serves as the precursor tothe Eastern half 22-OH.

New Chlorins. Chlorins bearing synthetic handles at defined locations atthe perimeter of the macrocycle are valuable building blocks for theconstruction of model systems in biomimetic or materials chemistry.Porphyrinic pigments bearing an ethyne group and an iodo group atdiametrically opposed positions are particularly attractive for theconstruction of linear multiporphyrin arrays (Wagner, et al. (1996) J.Am. Chem. Soc. 118:11166-11180). We have found that the extent ofelectronic communication between porphyrins of a given electroniccomposition depends on the site of attachment of a linker on themacrocycle (Strachan, et al. (1997) J. Am. Chem. Soc. 119:11191-11201;Yang, et al. (1999) J. Am. Chem. Soc. 121:4008-4018). Accordingly, theavailability of chlorins with diverse substitution patterns would enablestudy of such electronic effects in chlorins, complementing our priorstudies with porphyrins. For the construction of linear arrays,substitution at the 2- and 12-positions is quite attractive(Balasubramanian, et al. (2000) J. Org. Chem. 65:7919-7929). Theβ-substituted Eastern and Western halves are well suited for thisapplication. The reaction of 16 and 22-OH was performed using theprevious two-flask procedure, affording chlorin 23 in 7.8% yield (Scheme7). ¹H NMR spectroscopy confirmed the expected structure. The geminaldimethyl groups of 23 resonate as a singlet at δ 1.97, and the CH₂ inthe reduced pyrrole ring gives rise to a singlet downfield at δ 4.51.The four β-pyrrole hydrogens resonate in the region of δ 8.56-8.81. Theeight hydrogens of the aryl rings in the β-substituents of the chlorinresonate in the region of δ 7.82-8.14 as two pairs of doublets.

General Experimental Methods.

¹H and ¹³C NMR spectra (300 MHz) were collected in CDCl₃ unless notedotherwise. Absorption spectra (Cary 3, 0.25 nm data intervals) wereobtained at room temperature. Chlorins were analyzed by laser desorptionmass spectrometry (LD-MS) in the absence of a matrix (Fenyo, et al.(1997) J. Porphyrins Phthalocyanines 1-:93-99; Srinivasan et al. (1999)J. Porphyrins Phthalocyanines 3:283-291). Pyrrole was distilled atatmospheric pressure from CaH₂. Melting points are uncorrected.p-Iodobenzaldehyde was obtained from Karl Industries, Inc. All otherreagents and starting materials were obtained from Aldrich.Chromatography was performed using flash silica (Baker) or alumina(Fisher A540, 80-200 mesh).

Solvents. THF was distilled from sodium benzophenone ketyl. Toluene wasdistilled from CaH₂. CH₂Cl₂ was distilled from CaH₂. The CH₂Cl₂ employedfor extraction in the chlorin synthesis was distilled from CaH₂ andshaken with anhydrous Na₂CO₃ prior to use. CH₃CN (Fisher certifiedA.C.S.) was distilled from CaH₂ and stored over powdered molecularsieves. Nitromethane was stored over CaCl₂. Anhydrous methanol wasobtained as follows. Methanol received was dried over CaH₂ for 12 h, andthen was distilled. Other solvents were used as received.

Non-commercial compounds. The compounds 14 (Balasubramanian, et al.(2000) J. Org. Chem. 65:7919-7929) and 18 (Balasubramanian and Lindsey(1999) Tetrahedron 55:6771-6784) were prepared as described in theliterature.

1,3,3-Trimethyl-7-(4-iodophenyl)-2,3,4,5-tetrahydrodipyrrin N¹⁰-oxide(15). A solution of1-[3-(4-iodophenyl)pyrro-2-yl]-2-nitro-3,3-dimethyl-5-hexanone (14)(0.50 g, 1.14 mmol) in acetic acid (10 mL) was treated with zinc dust(1.74 g, 26.47 mmol) all-at-once and the mixture was stirred vigorouslyfor 1 h at room temperature. The crude reaction mixture was filtered(Celite) and concentrated. The residue was dissolved in CH₂Cl₂, washed(10% aq Na₂CO₃), dried (Na₂SO₄) and evaporated to afford a yellow solid.Recrystallization from ethyl acetate gave a white powder (200 mg, 43%yield): mp 173-174° C.; ¹H NMR δ 0.98 (s, 3H), 1.17 (s, 3H), 2.10 (s,3H), 2.36 (d, J=17.4 Hz, 1H),2.52 (d, J=17.4 Hz, 1H), 3.07 (m, 2H), 3.96(m, 1H), 6.20 (m, 1H), 6.74 (m, 1H), 7.08 (d, J=7.8 Hz, 2H), 7.67 (d,J=7.8 Hz, 2H), 11.31 (br, 1H); ¹³C NMR δ 13.2, 22.7, 23.5, 26.8, 37.8,46.8, 81.0, 90.1, 107.8, 117.0, 120.6, 125.7, 130.2, 137.0, 137.3,145.5; Anal. Calcd. for C₁₈H₂₁NIO₂: C, 52.95; H, 5.18; N, 6.86. Found:C, 52.91; H, 5.23; N, 6.78.

1,3,3-Trimethyl- 7-(4-iodophenyl)-2,3,4,5-tetrahydrodipyrrin (16).Following a procedure for the deoxygenation of N-oxides (EXAMPLE 1),TiCl₄ (1.0 mL, 8.8 mmol) was slowly added to a stirred solution of dryTHF (20 mL) under argon at 0° C. To the resulting yellow solution, LiAlH(223 mg, 5.9 mmol) was added slowly and the black mixture was stirred atroom temperature for 15 min, then triethylamine (7.7 mL) was added. Theblack mixture was then poured into a solution of 15 (500 mg, 1.22 mmol)in THF (20 mL). The mixture was stirred for 2 h at room temperature andthen water (20 mL) was added. The mixture was filtered to removeinorganic materials. The filtrate was extracted (CH₂Cl₂). The organiclayer was dried (Na₂SO₄) and evaporated under reduced pressure. Theresulting brown oil was purified by chromatography (silica, ethylacetate) to give a light brown oil which solidified on cooling (180 mg,38%): mp 90-91° C.; ¹H NMR δ 0.92 (s, 3H), 1.08 (s, 3H), 2.05 (s, 3H),2.34 (m, 2H), 2.59 (m,1H), 2.92 (m, 1H), 3.64 (d, J=11.7 Hz, 1H), 6.25(m, 1H), 6.73 (m, 1H), 7.13 (d, J=6.6 Hz, 2H), 7.66 (d, J=6.6 Hz, 2H),10.30 (br, 1H); ¹³C NMR δ 21.2, 23.5, 27.0, 27.8, 42.6, 54.9, 80.5,90.4, 108.4, 117.0, 120.3, 128.9, 130.6, 137.8, 137.9, 175.3; FAB-MSobsd 393.0841, calcd exact mass 393.0828 (C₁₈H₂₁IN₂).

1,3,3-Trimethyl-7-[4-[2-(trimethylsilyl)ethynyl]phenyl]-2,3,4,5-tetrahydrodipyrrin(17). Samples of 16 (450 mg, 1.15 mmol), Pd₂(dba)₃ (81 mg, 0.09 mmol),Ph₃As (219 mg, 0.72 mmol), and CuI (17 mg, 0.09 mmol) were added to a 50mL Schlenk flask. The flask was evacuated and purged with argon threetimes. Then deaerated anhydrous THF/triethylamine (12 mL, 1:1) was addedfollowed by (trimethylsilyl)acetylene (243 μL, 1.72 mmol). The flask wassealed, immersed in an oil bath (37° C.), and the mixture was stirredovernight. Then CH₂Cl₂ (30 mL) was added and the mixture was filtered(Celite) and washed (CH₂Cl₂). The filtrate was concentrated. Theresulting residue was purified by flash chromatography (silica, ethylacetate) to afford a dark brown viscous oil (316 mg, 76%): ¹H NMR δ 0.25(s, 9H), 0.92 (s, 3H), 1.07 (s, 3H), 2.05 (s, 3H), 2.34 (m, 2H), 2.61(m,1H), 2.96 (m, 1H), 3.65 (d, J=11.7 Hz, 1H), 6.29 (m, 1H), 6.74 (m,1H), 7.32 (d, J=7.8 Hz, 2H), 7.47 (d, J=7.8 Hz, 2H), 10.27 (br, 1H); ¹³CNMR δ 0.7, 21.1, 23.5, 27.1, 27.7, 42.6, 54.8, 80.5, 94.1, 106.3, 108.4,117.0, 119.8, 120.9, 128.3, 129.3, 132.7, 138.7, 175.4; FAB-MS obsd363.2271, calcd exact mass 363.2257 (C₂₃H₃₀N₂Si).

3-(4-Iodophenyl)-9-(3,5-di-tert-butylbenzoyl)-10-N-(tert-butoxycarbonyl)-dipyrromethane(19). A solution of 18 (896 mg, 2.0 mmol) in anhydrous THF (30 mL) underargon at 0° C. was treated slowly with EtMgBr (1M in THF, 6 mL, 6.0mmol). The mixture was stirred for 10 min at 0° C. Then a solution of3,5-di-tert-butylbenzoyl chloride (760 mg, 3.0 mmol) in anhydrous THF (5mL) was added slowly and stirring was continued for 1.5 h at 0° C. Thereaction was quenched with saturated aqueous NH₄Cl and extracted(CH₂Cl₂). The combined organic layers were washed with water and brine,dried (Na₂SO₄), and concentrated. The product was purified by flashcolumn chromatography [silica, hexanes/ethyl acetate (4:1)] to yield abrown viscous oil which was cooled overnight in the refrigerator. Aminimum amount of hexanes was added followed by sonication, affording awhite solid (598 mg, 45%): mp 178-179° C; ¹H NMR δ 1.35 (s, 18H), 1.58(s, 9H), 4.30 (s,2H), 5.97 (m, 1H), 6.26 (m, 1H), 6.73 (m, 1H), 7.11 (d,J=6.6 Hz, 2H), 7.30 (m, 1H), 7.60 (m, 1H), 7.70 (m, 2H), 7.72(m, 2H),9.92 (br, 1H); ¹³C NMR δ 25.8, 28.5, 32.0, 35.6, 85.5, 93.0, 110.1,112.3, 120.4, 122.1, 123.9, 126.3, 127.1, 128.2, 131.2, 131.3, 135.4,138.2, 138.6, 139.2, 150.5, 151.3, 185.7; Anal. Calcd for C₃₅H₄₁IN₂O₃:C, 63.25; H, 6.22; N, 4.21. Found: C, 64.03; H, 6.35; N, 4.15.

3-(4-Iodophenyl)-9-(3,5-di-tert-butylbenzoyl)dipyrromethane (20). Asolution of 19 (600 mg, 0.90 mmol) in anhydrous THF (10 mL) under argonat room temperature was treated with methanolic NaOMe (146 mg, 2.70mmol, in 1.0 mL of anhydrous methanol). After 10 min, the reaction wasquenched with a mixture of hexanes and water (20 mL, 1:1) and extractedwith ethyl acetate. The combined organic layers were washed with waterand brine, dried (Na₂SO₄), and concentrated. The residue wasrecrystallized from ethanol to give a pale brown solid (430 mg, 84%): mp202-203° C.; ¹H NMR δ 1.30 (s, 18H), 4.18 (s, 2H), 6.23 (m, 2H), 6.48(m, 1H), 6.93 (m, 1H), 7.25 (d, J=8.1 Hz, 2H),7.68 (m, 1H), 7.75 (m,4H), 10.23 (br, 1H), 11.85 (br, 1H); ¹³C NMR δ 25.6, 31.9, 35.6, 91.1,109.0, 111.2, 118.1, 121.6, 124.0, 124.2, 124.8, 127.0, 130.9, 131.5,137.3, 138.0, 138.2, 141.5, 151.8, 187.5; Anal. Calcd for C₃₀H₃₃IN₂O: C,63.83; H, 5.89; N, 4.96. Found: C, 63.74; H, 6.09; N, 5.00.

3-[4-[2-Trimethylsilyl)ethynyl]phenyl]-9-(3,5-di-tert-butylbenzoyl)dipyrromethane(21). Samples of 20 (1.0 g, 1.77 mmol), Pd₂(dba)₃ (125 mg, 0.14 mmol),Ph₃As (334 mg, 1.09 mmol), and CuI (26 mg, 0.14 mmol) were added to a 50mL Schlenk flask. The flask was evacuated and purged with argon threetimes. Then deaerated anhydrous THF/triethylamine (18 mL, 1:1) was addedfollowed by (trimethylsilyl)acetylene (376 μL, 2.66 mmol). The flask wassealed, immersed in an oil bath (37° C.), and the mixture was stirredovernight (16-18 h). Then CH₂Cl₂ (30 mL) was added and the mixture wasfiltered (Celite) and washed (CH₂Cl₂). The filtrate was concentrated.The resulting residue was purified by flash chromatography [silica,hexanes/ethyl acetate (3:1)] to afford a yellow oil which solidified oncooling (780 mg, 82%): mp 126-127° C.; ¹H NMR δ 0.26 (s, 9H), 1.27 (s,18H), 4.20 (s, 2H), 6.20 (m, 2H), 6.44 (m,1H), 6.87 (m, 1H), 7.40 (d,J=8.1 Hz, 2H), 7.50 (d, J=8.1 Hz, 2H), 7.64 (m, 1H), 7.72 (m, 2H), 10.14(br, 1H), 11.73 (br, 1H); ¹³C NMR δ 0.7, 25.7, 31.9, 35.5, 94.4, 106.2,109.1, 111.1, 118.1, 120.4, 122.0, 123.9, 124.1, 124.9, 126.9, 128.5,131.5, 132.7, 138.1, 138.2, 141.3, 151.7, 187.45; Anal. Calcd forC₂₈H₂₈N₂OSi: C, 78.60; H, 7.92; N, 5.24. Found: C, 78.09; H, 8.03; N,5.13.

1-Bromo-3-[4-[2-(trimethylsilyl)ethynyl]phenyl]-9-(3,5-di-tert-butylbenzoyl)-dipyrromethane(22). A solution of 21 (100 mg, 0.19 mmol) in anhydrous THF (6 mL) wascooled to −78° C. under argon. Recrystallized NBS (33 mg 0Q.19 mmol) wasadded and the reaction mixture was stirred for 1 h (−78° C.), then themixture was quenched with a mixture of hexanes and water (20 mL, 1:1)and allowed to warm to 0° C. The aqueous portion was extracted withanhydrous ether and the combined organic layers were dried (K₂CO₃). Thesolvent was evaporated under vacuum without heating. Purification byflash chromatography [silica, hexanes/ether (2:1)] afforded a paleyellow solid (83 mg, 72%): mp 163-165° C. (dec.); ¹H NMR δ 0.27 (s, 9H),1.30 (s, 18H), 4.20 (s, 2H), 6.08 (m, 1H), 6.23 (m, 1H), 6.94 (m, 1H),7.36 (d, J=7.8 Hz, 2H), 7.52 (d, J=7.8 Hz, 2H), 7.66 (s, 1H), 7.74 (s,2H), 10.75 (br, 1H), 12.14 (br, 1H); ¹³C NMR δ 0.7, 24.8, 31.2, 34.9,94.0, 97.9, 105.2, 110.0, 110.7, 120.3, 123.1, 123.7, 123.8, 125.5,126.5, 127.9, 130.8, 132.0, 136.3, 137.3, 140.5, 151.1, 187.3; Anal.Calcd for C₃₅H₄₁BrN₂OSi: C, 68.50; H, 6.73; N, 4.56. Found: C, 68.06; H,6.64; N, 4.49; FAB-MS obsd 612.2184, calcd exact mass 612.2172(C₃₅H₄₁BrN₂OSi).

Zn(II)-17,18-Dihydro-18,18-dimethyl-2-(4-iodophenyl)-5-(3,5-di-tert-butylbenzoyl)-12-[4-[2-(trimethylsilyl)ethynyl]phenyl]porphyrin(23). Following the two-flask procedure (EXAMPLE 1), to a solution of 22(123 mg, 0.20 mmol) in anhydrous THF/methanol (7.5 mL, 4:1) was addedexcess NaBH4 (100 mg, 2.60 mmol) in small portions at room temperature.The reaction was monitored by TLC [alumina, hexanes/ethyl acetate(1:1)]. Upon completion, the reaction mixture was quenched with coldwater (10 mL), then extracted with distilled CH₂Cl₂ (3×25 mL). Thecombined organic layers were washed with brine (50 mL), dried (K₂CO₃)and concentrated in vacuo without heating to leave the resultingcarbinol 22-OH in ˜1-2 mL of CH₂Cl₂. A solution of1,3,3-trimethyl-7-(4-iodophenyl)-2,3,4,5-tetrahydrodipyrrin (16) (78 mg,0.20 mmol) in a few milliliters of anhydrous CH₃CN was combined with thecarbinol, then additional anhydrous CH₃CN was added to give a total of20 mL of CH₃CN. The solution was stirred at room temperature under argonand TFA (20 μL, 0.26 mmol) was added. The reaction was monitored by TLC[alumina, hexanes/ethyl acetate (3:1)]; after 1 h the carbinol haddisappeared. The reaction mixture was quenched with 10% aqueous NaHCO₃and extracted with distilled CH₂Cl₂ (3×25 mL). The combined organiclayers were washed with water and brine, then dried (Na₂SO₄). Thesolvent was removed in vacuo at room temperature. The residue wasdissolved in 14, mL of anhydrous toluene under argon, then AgIO₃ (848mg, 3.0 mmol), piperidine (300 μL, 3.0 mmol) and Zn(OAc)₂ (550 mg, 3.0mmol) were added. The resulting mixture was heated at 80° C. for 3 h.The reaction was monitored by TLC [silica, hexanes/CH₂Cl₂ (1:1); showinga single green spot]. The mixture was cooled to room temperature, thenpassed through a short column (silica, CH₂Cl₂). The major fraction wasconcentrated and again chromatographed [silica, hexanes/CH₂Cl₂ (2:1 then1:1)] to give a greenish blue solid (15 mg, 7.8%): ¹H NMR δ 0.35 (s,9H), 1.51 (s, 18H), 1.97 (s, 6H), 4.51 (s, 2H), 7.42 (s,1H), 7.82 (d,J=9.0 Hz, 2H), 7.87 (d, J=7.8 Hz, 2H), 7.96 (m, 2H), 8.03 (d, J=8.1 Hz,2H), 8.14 (d, J=8.1 Hz, 2H), 8.56 (d, J=4.5 Hz, 1H), 8.66 (m, 2H), 8.72(m, 2H), 8.81 (d, J=4.5 Hz, 1H), 9.61 (s, 1H); LD-MS obsd 964.60; FAB-MSobsd 964.2382, calcd exact mass 964.2376 (C₅₃H₅₃IN₄SiZn); λ_(abs)(toluene)/nm 417 (log ε=5.30, fwhm=20 nm), 629 (4.86); λ_(em) 634, 691nm.

Conclusions. We have developed a tetrahydrodipyrrin Western half for thesynthesis of chlorin building blocks. The new Western Half is obtainedvia the reductive cyclization of a nitro-hexanone substituted pyrrolefollowed by mild deoxygenation with a Ti(0) reagent. Thetetrahydrodipyrrin is more stable than the dihydrodipyrrin usedpreviously. The facile condensation of the Eastern half and Western halfis performed at room temperature for a few minutes. The oxidativecyclization is performed at 80° C. for several hours in the presence ofa zinc template. The tetrahydrobilene-a formed in the condensation ofthe Eastern and Western halves has been isolated and found to bereasonably stable. A one-flask synthetic procedure for chlorin formationhas been developed. Several zinc chlorins were synthesized, with yieldsof 9 to 19% in the ring-forming step.

EXAMPLE 3 Isolation and Characterization of a 2-iodo-chlorin Byproduct

During our initial synthesis of a chlorin using the tetrahydrodipyrrinWestern half, we employed the condensation and oxidation conditions(Strachan, et al. (2000) J. Org. Chem. 65:3160-3172) developed for thedipyrrin Western half. Thus, a reaction was performed of 4 and aniodo-phenyl substituted Eastern half (6g-OH) in acetonitrile containing10 mM TFA followed by oxidative cyclization using AgIO₃, Zn(OAc)₂, andpiperidine in toluene at 80° C. (Scheme 8). In addition to the desiredchlorin (Zn-8h), we identified a byproduct upon examination of the LD-MSspectrum. The LD-MS spectrum shows peaks at m/z=694 and 820, the formerof which corresponds to the desired chlorin Zn-8h. This Δm of 126 isascribed to the presence of an iodo atom (note that the chlorin targetmolecule bears a single iodo group; the byproduct bears two iodogroups). However, only a single chlorin spot was observed upon TLCanalysis. The absorption spectrum in the Q_(y)(0,0) region was somewhatbroad. Upon demetalation of the zinc-chlorin material, TLC analysisshowed the presence of two chlorin species. Isolation andcharacterization (particularly with ¹H NMR and NOE experiments) revealedthat the iodination occurred regiospecifically at the 2-position. Wenote that this iodinated byproduct may have useful syntheticapplications. The following experimental section describes the isolationand characterization data for the 2-iodo-chlorin byproduct.

Synthesis of17,18-dihydro-18,18-dimethyl-5-(4-methylphenyl)-10-(4-iodophenyl)-porphyrin(Fb-8g) and17,18-dihydro-18,18-dimethyl-5-(4-methylphenyl)-2-iodo-10-(4-iodophenyl)porphyrin(Fb-8h). Following the general procedure, treatment of 6g (272 mg, 0.500mmol) with NaBH₄ (114 mg, 3.01 mmol) in 7.5 mL of anhydrous THF/methanol(4:1) afforded 6g-OH. The residue was dissolved in 50 mL of anhydrousCH₃CN. 1,3,3-trimethyl-2,3,4,5-tetrahydrodipyrrin (4, 100 mg- 0.530mmol) was added following TFA (38 μL, 0.50 mmol, 10 mM). The solutionwas stirred at room temperature for 30 min. The reaction was quenchedwith 10% aqueous NaHCO₃ (50 mL) and extracted with distilled CH₂CL₂(3×50 mL). The combined organic layers were washed with water, dried(Na₂CO₃) and concentrated in vacuo without heating. The residue wasdissolved in 50 mL of toluene, to which AgIO₃ (2.12 g, 7.50 mmol),Zn(OAc)₂ (1.38 g, 7.50 mmol) and piperidine (740 μL, 7.50 mmol) wereadded. The reaction mixture was heated at 80° C. exposed to air for 2 h.The reaction mixture was concentrated under reduced pressure. Theresidue was passed through a short silica gel column eluting withCH₂Cl₂. The major fraction was concentrated and again chromatographed onsilica eluting with hexanes/CH₂Cl₂ (2:1) to afford a blue solid (66.mg).From the blue solid, 56 mg was taken and dissolved in 10 mL of CH₂Cl₂and treated with TFA (310 μL, 4.04 mmol). The demetalation was completein 1 h as confirmed by UV-Vis and TLC analyses. Then 70 mL of CH₂Cl₂ and2 mL of triethylamine were added to the reaction mixture. The mixturewas washed with saturated aqueous NaHCO₃ (100 mL×2) and dried (Na₂SO₄).TLC analysis [silica, hexanes/CH₂Cl₂ (1:1)] showed two components: aformer component (R_(f)=0.72; Fb-8h) and a latter component (R_(f)=0.57;Fb-8g). The solvent was removed under vacuum. Chromatography of theresidue [silica, hexanes/CH₂Cl₂ (3:1)] afforded Fb-8g (32 mg, 12%) andFb-8h (19 mg, 6%). Analytical data of Fb-8g are consistent with theliterature values (Strachan, et al. (2000) J. Org. Chem. 65:3160-3172).Fb-8h: ¹H NMR 6-1.66 (bs, 2H), 2.07 (s, 6H), 2.67 (s, 3H), 4.58 (s, 2H),7.51 (d, J=8.1 Hz, 2H), 7.82 (d J=8.1 Hz, 2H), 7.96 (d, J=8.1 Hz, 2H),8.03 (d J=8.1 Hz, 2H), 8.40 (d, J=4.4 Hz, 1H), 8.48 (d, J=4.4 Hz, 1H),8.70 (d, J=4.4 Hz, 1H), 8.77 (d, J=4.4 Hz, 1H), 8.88 (s, 1H), 8.95 (s,1H), 8.97 (s, 1H); LD-MS obsd 757.24; FAB-MS obsd 759.0480, calcd759.0482 (C₃₅H₂₈I₂N₄); λ_(abs) (toluene) 420, 512, 649 nm.

The foregoing is illustrative of the present invention, and is not to beconstrued as limiting thereof. The invention is defined by the followingclaims, with equivalents of the claims to be included therein.

1-15. (canceled)
 16. A method of making a tetrahydrobilene of FormulaXI:

wherein: K¹, K² and K⁴ are hetero atoms independently selected from thegroup consisting of N, O, S, Se, Te, and CH; K³ is N; S¹, S², S^(3,) S⁴S^(5,) S^(6,) S^(7,) S^(8,) S^(9,) S^(10,) S^(11,) S^(12,) S^(13,) andS¹⁴ are independently selected from the group consisting of H, aryl,phenyl, cycloalkyl, alkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio,perfluoroalkyl, perfluoroaryl, pyridyl, cyano, thiocyanato, nitro,amino, alkylamino, acyl, sulfoxyl, sulfonyl, imido, amido, andcarbamoyl; and wherein from one to four of S¹, S², S^(3,) S⁴ S^(5,)S^(6,) S^(7,) S^(8,) S^(9,) S¹⁰, S¹¹, S¹², S¹³, and S¹⁴ may optionallybe independently selected linking groups Q, wherein said linking groupsQ are of the formula:R¹—R²_(n)R³—Y wherein: n is from 0 to 10; R³ may be present or absent;R¹, R^(2,) and R³ are each independently selected from the groupconsisting of ethene, ethyne, aryl, and heteroaryl groups, which aryland heteroaryl groups may be unsubstituted or substituted one or moretimes with H, aryl, phenyl, cycloalkyl, alkyl, alkenyl, alkynyl,halogen, alkoxy, alkylthio, perfluoroalkyl, perfluoroaryl, pyridyl,cyano, thiocyanato, nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl,imido, amido, and carbamoyl; Y is a protected or unprotected reactivesubstituent selected from the group consisting of hydroxy, thio, seleno,telluro, ester, carboxylic acid, boronic acid, phenol, silane, sulfonicacid, phosphonic acid, alkylthiol, formyl, halo, alkenyl, alkynyl,haloalkyl, alkyl phosphonate, alkyl sulfonate, alkyl carboxylate, andalkyl boronate groups; and Z is selected from the group consisting ofhalo, alkoxy, and acyloxy; said method comprising condensing a compoundof Formula WH with a compound of Formula EH

in an organic solvent in the presence of an acid to form atetrahydrobilene of Formula XI.
 17. The method according to claim 16,wherein said acid is a Bronsted or Lewis acid.
 18. The method accordingto claim 16, wherein said acid is trifluoroacetic acid.
 19. The methodaccording to claim 16, wherein said condensing step is carried out undernonaqueous conditions.
 20. The method according to claim 16, whereinsaid organic solvent is a polar or nonpolar aprotic solvent.
 21. Themethod according to claim 16, wherein said organic solvent isacetonitrile, tetrahydrofuran or a mixture thereof.
 22. Atetrahydrobilene of Formula XI:

wherein: K¹, K² and K⁴ are hetero atoms independently selected from thegroup consisting of N, O, S, Se, Te, and CH; K³ is N; S¹, S², S^(3,) S⁴S^(5,) S^(6,) S⁷S^(8,) S^(9,) S^(10,) S^(11,) S^(12,) S^(13,) and S¹⁴are independently selected from the group consisting of H, aryl, phenyl,cycloalkyl, alkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio,perfluoroalkyl, perfluoroaryl, pyridyl, cyano, thiocyanato, nitro,amino, alkylamino, acyl, sulfoxyl, sulfonyl, imido, amido, andcarbamoyl; and wherein from one to four of S¹, S^(2,) S^(3,) S⁴ S^(5,)S^(6,) S^(7,)S^(8,) S^(9,) S^(10,) S^(11,) S^(12,) S^(13,) and S¹⁴ mayoptionally be independently selected linking groups Q, wherein saidlinking groups Q are of the formula:R¹—R²_(n)R³—Y wherein: n is from 0to 10; R³ may be present or absent;R¹, R^(2,) and R³ are each independently selected from the groupconsisting of ethene, ethyne, aryl, and heteroaryl groups, which aryland heteroaryl groups may be unsubstituted or substituted one or moretimes with H, aryl, phenyl, cycloalkyl, alkyl, alkenyl, alkynyl,halogen, alkoxy, alkylthio, perfluoroalkyl, perfluoroaryl, pyridyl,cyano, thiocyanato, nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl,imido, amido, and carbamoyl; Y is a protected or unprotected reactivesubstituent selected from the group consisting of hydroxy, thio, seleno,telluro, ester, carboxylic acid, boronic acid, phenol, silane, sulfonicacid, phosphonic acid, alkylthiol, formyl, halo, alkenyl, alkynyl,haloalkyl, alkyl phosphonate, alkyl sulfonate, alkyl carboxylate, andalkyl boronate groups; and Z is selected from the group consisting ofhalo, alkoxy, and acyloxy.
 23. The tetrahydrobilene according to claim22, wherein S¹ and S⁵ are independently selected trans-substitutedlinking groups Q.
 24. The tetrahydrobilene according to claim 22,wherein S² and S⁶ are independently selected trans-substituted linkinggroups Q.
 25. The tetrahydrobilene according to claim 22, wherein K¹, K²and K⁴ are independently selected from the group consisting of N, O, S,and CH.
 26. The tetrahydrobilene according to claim 22, wherein K¹, K²and K⁴ are all N.
 27. The tetrahydrobilene according to claim 22,wherein S¹, S², S^(3,) S^(4,) S^(5,) S^(6,) S^(7,) S^(8,) S^(9,) S^(10,)S^(11,) S^(12,) S^(13,) and S¹⁴ are all alkyl.
 28. A compound of FormulaWH:

wherein: K¹ is selected from the group consisting of N, O, S, Se, Te,and CH; S¹, S², S⁷, S^(8,) S¹, S^(12,) S^(13,) and S¹⁴ are independentlyselected from the group consisting of H, aryl, phenyl, cycloalkyl,alkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio, perfluoroalkyl,perfluoroaryl, pyridyl, cyano, thiocyanato, nitro, amino, alkylamino,acyl, sulfoxyl, sulfonyl, imido, amido, and carbamoyl; and wherein fromone to two of S¹, S², S⁷, S^(8,) S^(9,) S^(12,) S^(13,) and S¹⁴ mayoptionally be independently selected linking groups Q, wherein saidlinking groups Q are of the formula:R¹—R²_(n)R³—Y wherein: n is from 0 to 10; R³ may be present or absent;R¹, R^(2,) and R³ are each independently selected from the groupconsisting of ethene, ethyne, aryl, and heteroaryl groups, which aryland heteroaryl groups may be unsubstituted or substituted one or moretimes with H, aryl, phenyl, cycloalkyl, alkyl, alkenyl, alkynyl,halogen, alkoxy, alkylthio, perfluoroalkyl, perfluoroaryl, pyridyl,cyano, thiocyanato, nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl,imido, amido, and carbamoyl; and Y is a protected or unprotectedreactive substituent selected from the group consisting of hydroxy,thio, seleno, telluro, ester, carboxylic acid, boronic acid, phenol,silane, sulfonic acid, phosphonic acid, alkylthiol, formyl, halo,alkenyl, alkynyl, haloalkyl, alkyl phosphonate, alkyl sulfonate, alkylcarboxylate, and alkyl boronate groups; subject to the proviso that S¹and S² are not simultaneously alkyl.
 29. The compound according to claim28, subject to the proviso that S¹ and S² are not simultaneously alkylor H.
 30. The compound according to claim 28, wherein S¹ is selectedfrom the group consisting of Q, aryl, phenyl, cycloalkyl, alkenyl,alkynyl, halogen, alkoxy, alkylthio, perfluoroalkyl, perfluoroaryl,pyridyl, cyano, thiocyanato, nitro, amino, alkylamino, acyl, sulfoxyl,sulfonyl, imido, amido, and carbamoyl.
 31. The compound according toclaim 28, wherein S² is selected from the group consisting of Q, aryl,phenyl, cycloalkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio,perfluoroalkyl, perfluoroaryl, pyridyl, cyano, thiocyanato, nitro,amino, alkylamino, acyl, sulfoxyl, sulfonyl, imido, amido, and carbamoyl32. The compound according to claim 28, wherein S¹ is a linking group Q.33. The compound according to claim 28, wherein S² is a linking group Q.34. The compound according to claim 28, wherein K¹ is selected from thegroup consisting of N, O, S, Se and Te.
 35. The compound according toclaim 28, wherein K¹ is N.
 36. The compound according to claim 28,wherein S¹, S², S⁷, S^(8,) S^(9,) S^(12,) S^(13,) and S¹⁴ are all alkyl.37. A method of making a compound of Formula WH:

wherein: K¹ is selected from the group consisting of N, O, S, Se, Te,and CH; S^(1,) S², S⁷, S⁸, S^(9,) S^(12,) S^(13,) and S¹⁴ areindependently selected from the group consisting of H, aryl, phenyl,cycloalkyl, alkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio,perfluoroalkyl, perfluoroaryl, pyridyl, cyano, thiocyanato, nitro,amino, alkylamino, acyl, sulfoxyl, sulfonyl, imido, amido, andcarbamoyl; and wherein from one to two of S¹, S², S⁷, S^(8,) S^(9,)S^(12,) S^(13,) and S¹⁴ may optionally be independently selected linkinggroups Q, wherein said linking groups Q are of the formula:R¹—R²_(n)R³—Y wherein: n is from 0 to 10; R³ may be present or absent;R¹, R^(2,) and R³ are each independently selected from the groupconsisting of ethene, ethyne, aryl, and heteroaryl groups, which aryland heteroaryl groups may be unsubstituted or substituted one or moretimes with H, aryl, phenyl, cycloalkyl, alkyl, alkenyl, alkynyl,halogen, alkoxy, alkylthio, perfluoroalkyl, perfluoroaryl, pyridyl,cyano, thiocyanato, nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl,imido, amido, and carbamoyl; Y is a protected or unprotected reactivesubstituent selected from the group consisting of hydroxy, thio, seleno,telluro, ester, carboxylic acid, boronic acid, phenol, silane, sulfonicacid, phosphonic acid, alkylthiol, formyl, halo, alkenyl, alkynyl,haloalkyl, alkyl phosphonate, alkyl sulfonate, alkyl carboxylate, andalkyl boronate groups; said method comprising reacting a compound ofFormula III

in an organic solvent in the presence of Ti(0) to form the compound ofFormula WH.
 38. A compound according to Formula III:

wherein: K¹ is selected from the group consisting of N, O, S, Se, Te,and CH; S¹, S², S⁷, S⁸, S^(9,) S^(12,) S^(13,) and S¹⁴ are independentlyselected from the group consisting of H, aryl, phenyl, cycloalkyl,alkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio, perfluoroalkyl,perfluoroaryl, pyridyl, cyano, thiocyanato, nitro, amino, alkylamino,acyl, sulfoxyl, sulfonyl, imido, amido, and carbamoyl; and wherein fromone to two of S^(1,) S², S⁷, S^(8,) S^(9,) S^(2,) S^(13,) and S¹⁴ mayoptionally be independently selected linking groups Q, wherein saidlinking groups Q are of the formula:R¹—R²_(n)R³—Y wherein: n is from 0 to 10; R³ may be present or absent;R¹, R^(2,) and R³ are each independently selected from the groupconsisting of ethene, ethyne, aryl, and heteroaryl groups, which aryland heteroaryl groups may be unsubstituted or substituted one or moretimes with H, aryl, phenyl, cycloalkyl, alkyl, alkenyl, alkynyl,halogen, alkoxy, alkylthio, perfluoroalkyl, perfluoroaryl, pyridyl,cyano, thiocyanato, nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl,imido, amido, and carbamoyl; and Y is a protected or unprotectedreactive substituent selected from the group consisting of hydroxy,thio, seleno, telluro, ester, carboxylic acid, boronic acid, phenol,silane, sulfonic acid, phosphonic acid, alkylthiol, formyl, halo,alkenyl, alkynyl, haloalkyl, alkyl phosphonate, alkyl sulfonate, alkylcarboxylate, and alkyl boronate groups.
 39. A method of making acompound of Formula III:

wherein: K¹ is selected from the group consisting of N, O, S, Se, Te,and CH; S¹, S², S⁷, S⁸, S^(9,) S^(12,) S^(13,) and S¹⁴ are independentlyselected from the group consisting of H, aryl, phenyl, cycloalkyl,alkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio, perfluoroalkyl,perfluoroaryl, pyridyl, cyano, thiocyanato, nitro, amino, alkylamino,acyl, sulfoxyl, sulfonyl, imido, amido, and carbamoyl; and wherein fromone to two of S^(1,) S², S⁷, S^(8,) S^(9,) S^(12,) S^(13,) and S¹⁴ mayoptionally be independently selected linking groups Q, wherein saidlinking groups Q are of the formula:R¹—R²_(n)R³—Y wherein: n is from 0 to 10; R³ may be present or absent;R¹, R^(2,) and R³ are each independently selected from the groupconsisting of ethene, ethyne, aryl, and heteroaryl groups, which aryland heteroaryl groups may be unsubstituted or substituted one or moretimes with H, aryl, phenyl, cycloalkyl, alkyl, alkenyl, alkynyl,halogen, alkoxy, alkylthio, perfluoroalkyl, perfluoroaryl, pyridyl,cyano, thiocyanato, nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl,imido, amido, and carbamoyl; and Y is a protected or unprotectedreactive substituent selected from the group consisting of hydroxy,thio, seleno, telluro, ester, carboxylic acid, boronic acid, phenol,silane, sulfonic acid, phosphonic acid, alkylthiol, formyl, halo,alkenyl, alkynyl, haloalkyl, alkyl phosphonate, alkyl sulfonate, alkylcarboxylate, and alkyl boronate groups; comprising cyclizing a compoundof Formula II:

in an organic solvent under reducing conditions to produce a compound ofFormula III.
 40. A compound of Formula II:

wherein: K¹ is selected from the group consisting of N, O, S, Se, Te,and CH; S¹, S², S⁷, S^(8,) S^(9,) S^(12,) S^(13,) and S¹⁴ areindependently selected from the group consisting of H, aryl, phenyl,cycloalkyl, alkyl, alkenyl, alkynyl, halogen, alkoxy, alkylthio,perfluoroalkyl, perfluoroaryl, pyridyl, cyano, thiocyanato, nitro,amino, alkylamino, acyl, sulfoxyl, sulfonyl, imido, amido, andcarbamoyl; and wherein from one to two of S¹, S², S⁷, S^(8,) S^(9,)S^(12,) S^(13,) and S¹⁴ may optionally be independently selected linkinggroups Q, wherein said linking groups Q are of the formula:R¹—R²_(n)R³—Y wherein: n is from 0 to 10; R³ may be present or absent;R¹, R^(2,) and R³ are each independently selected from the groupconsisting of ethene, ethyne, aryl, and heteroaryl groups, which aryland heteroaryl groups may be unsubstituted or substituted one or moretimes with H, aryl, phenyl, cycloalkyl, alkyl, alkenyl, alkynyl,halogen, alkoxy, alkylthio, perfluoroalkyl, perfluoroaryl, pyridyl,cyano, thiocyanato, nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl,imido, amido, and carbamoyl; and Y is a protected or unprotectedreactive substituent selected from the group consisting of hydroxy,thio, seleno, telluro, ester, carboxylic acid, boronic acid, phenol,silane, sulfonic acid, phosphonic acid, alkylthiol, formyl, halo,alkenyl, alkynyl, haloalkyl, alkyl phosphonate, alkyl sulfonate, alkylcarboxylate, and alkyl boronate groups.
 41. A compound of Formula X:

wherein: M is a metal selected from the group consisting of Cu, Zn, Mg,Pt, Pd, Sn and Al, or M is absent; K¹, K² and K⁴ are hetero atomsindependently selected from the group consisting of N, O, S, Se, Te, andCH; K³ is N; S^(1,) S^(2,) S^(3,) S⁴ S^(5,) S^(6,) S^(8,) S^(9,) S^(10,)S^(11,) S^(12,) and S¹⁴ are independently selected from the groupconsisting of H, aryl, phenyl, cycloalkyl, alkyl, alkenyl, alkynyl,halogen, alkoxy, alkylthio, perfluoroalkyl, perfluoroaryl, pyridyl,cyano, thiocyanato, nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl,imido, amido, and carbamoyl; S⁷ and S¹³ are together=0; and wherein fromone to four of S^(1,) S^(2,) S^(3,) S⁴ S^(5,) S^(6,) S^(7,) S^(8,)S^(9,) S^(10,) S^(11,) S^(12,) S^(13,) and S¹⁴ are independentlyselected linking groups Q, wherein said linking groups Q are of theformula:R¹—R²_(n)R³—Y wherein: n is from 0 to 10; R³ may be present or absent;R¹, R^(2,) and R³ are each independently selected from the groupconsisting of ethene, ethyne, aryl, and heteroaryl groups, which aryland heteroaryl groups may be unsubstituted or substituted one or moretimes with H, aryl, phenyl, cycloalkyl, alkyl, alkenyl, alkynyl,halogen, alkoxy, alkylthio, perfluoroalkyl, perfluoroaryl, pyridyl,cyano, thiocyanato, nitro, amino, alkylamino, acyl, sulfoxyl, sulfonyl,imido, amido, and carbamoyl; and Y is a protected or unprotectedreactive substituent selected from the group consisting of hydroxy,thio, seleno, telluro, ester, carboxylic acid, boronic acid, phenol,silane, sulfonic acid, phosphonic acid, alkylthiol, formyl, halo,alkenyl, alkynyl, haloalkyl, alkyl phosphonate, alkyl sulfonate, alkylcarboxylate, and alkyl boronate groups.
 42. The compound according toclaim 41, wherein S¹ is a linking group Q.
 43. The compound according toclaim 41, wherein S¹ is iodo.